Research Studies

Dr. Kari Lavik is a postdoctoral fellow at the University of Michigan in the laboratory of Dr. Jordan Shavit. She received a B.A. in biology from Case Western Reserve University, and her Ph.D. in Biomedical Sciences from The University of Toledo. Her graduate work focused on the study of cancer motility and metastasis through which she became interested in using zebrafish as a model for human disease. In February of 2017, Dr. Lavik joined the Shavit Laboratory in the Department of Pediatrics at the University of Michigan to use zebrafish for the study of bleeding and clotting disorders. For her 2018 JGP fellowship project, she will model hemophilia in the zebrafish, looking for novel species-specific regulators of hemostasis. By delving deeper into the genetic mechanisms that underlie the intrinsic pathway in zebrafish, Dr. Lavik will look for novel gene interactions that can be therapeutically targeted in patients with hemophilia.

The primary aim of this study is to determine if people with bleeding disorders and chronic pain will attend and find benefit from an 8-week mindfulness-based yoga program. This program was chosen because of its focus on building skills in the areas of gentle yoga and mindfulness. Yoga positions will be modified to meet the needs of people who have joint contractures and limited range of motion. The program will include instruction in yoga and meditation techniques that are designed to reduce pain, fatigue, psychological distress, sleeping disturbances, and increase functional capacity.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans, but there are numerous barriers to accurate and timely diagnosis. In January 2021, new evidence-based guidelines were released by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) (James et al., 2021). The guidelines were designed to support patients, clinicians, and other health care professionals in promptly, accurately, and efficiently diagnosing VWD. Key recommendations in the guidelines include the use of bleeding-assessment tools when unusual bleeding is present and/or VWD is suspected; diagnostic assays; and the role of genetic vs. phenotypic testing for some types of VWD. Nurse practitioners can aid in identifying potential symptoms of VWD to help shorten the time from onset of symptoms to diagnosis.
 

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Objective:

The Centers for Disease Control and Prevention (CDC) conducts inhibitor testing for the Community Counts Registry for Bleeding Disorders Surveillance, a public health monitoring program led by CDC’s Division of Blood Disorders along with its partners, the American Thrombosis and Hemostasis Network, and the U.S. Hemophilia Treatment Center Network.

Inhibitor testing at CDC involves a panel of inhibitor-related tests, including a CDC-modified Nijmegen-Bethesda assay (NBA), a chromogenic Bethesda assay (CBA) (for hemophilia A only), fluorescence immunoassays (FLI), and dilute Russell viper venom time (DRVVT).  An algorithm aimed at reducing false positive inhibitor results that utilizes this panel of tests has been developed by CDC.  Several novel hemophilia treatment products, including extended half-life factor products and a bi-specific antibody that mimics clotting factor VIII (emicizumab), have been approved by the US Food and Drug Administration (FDA).  CDC has validated inhibitor testing methods in the context of these novel treatment products and adjusted the testing algorithm when appropriate.  The objective of this analysis is to demonstrate the impact of novel hemophilia treatment products on the CDC inhibitor testing workflow for Community Counts.

Methods:

The number and relative proportions of NBA, CBA, FLI, and DRVVT results reported for Community Counts were compared across fiscal years 2018 (10/1/2017-9/30/2018) and 2019 (10/1/2018-9/30/2019).  Because emicizumab interferes with the NBA, all specimens from patients using emicizumab are subjected to an alternative testing algorithm that excludes the NBA and tests all specimens with the CBA.  The proportion of CBA results reported because the specimen was subjected to this alternative algorithm was also compared across fiscal years.

Summary:

CDC has reported over 11,500 inhibitor test results on over 10,000 specimens for Community Counts (Table).  The introduction of novel treatment products has shifted the types of factor VIII tests the CDC conducts.  Between 2018 and 2019, the proportion of results reported that were NBA results decreased 12%, whereas the proportion of results reported that were CBA or FLI results increased (125% and 150%, respectively).  This shift appears to be driven by the introduction of emicizumab.  The proportion of CBA tests conducted because the specimen was low-positive decreased 64%, but the proportion of CBA tests conducted because the patient was currently using emicizumab increased 150%.

Conclusions:

The introduction of novel hemophilia treatment products, notably emicizumab, has impacted the CDC inhibitor testing workflow for Community Counts.  Future efforts to validate the currently-used inhibitor testing algorithm in order to assure the algorithm is efficient, cost-effect, and accurate are needed.

Objective:

To facilitate a successful transition to home infusion therapy using virtual visits. This will decrease the number of emergency department (ED) or clinic visits, minimize delay in treatment of bleeding episodes in patients with hemophilia and facilitate compliance with COVID guidelines to reduce the number of patient contacts and use of personal protective equipment (PPE).

Background:

Patients and caregivers who are not independent in home infusion therapy traditionally require the services of a home care nurse or hospital/clinic visit in order to administer intravenous factor to treat their bleeding disorder. This is of particular concern in light of the current COVID-19 pandemic where contact outside one’s immediate family is discouraged, and non-emergent hospital visits are suspended. Infusion of factor at home by the patient/caregiver means that bleeding episodes can be treated in a timely and cost effective manner, resulting in decreased prolonged bleeding and fewer long-term complications.

The difference in cost and utilization of resources is substantial. Past studies have shown that an average ED visit costs around two to three thousand dollars. These costs and the need for a home nurse can be avoided when the family is independent with infusion. Delay in treatment of an acute bleeding episode is avoidable when a patient or caregiver is able to infuse factor in the home.

Methods:

We utilized the Doxy.me telehealth platform for virtual training and support of home infusions, using the group call feature of the program. The two patients were 3 and 20 years old males with severe hemophilia B. Both patients and caregivers were introduced to the basic infusion skills during in-person clinic visits. The COVID Era concerns raised the urgency and challenges to institute home therapy. A virtual visit was scheduled which coincided with the timing of the patients’ regular prophylactic factor dose. Hemostasis Center (HTC) RNs as well as the provider were present on the call to provide support and assistance with vein selection and infusion technique, guiding the patient/caregiver and talking through the process.

Conclusion:

Both patients were successful in home infusion therapy with the virtual support of the HTC staff. This method allowed the HTC staff the unique opportunity to observe and support the family in their home setting while reducing cost. Both patients and caregivers were given a brief survey in follow-up phone calls, and all reported increased confidence with home factor infusion skills. All gave positive feedback regarding the virtual visit method. One parent viewed the virtual visit as a productive last step in the learning process of home factor infusion. Both patients continue to be successful with home factor infusion after the initial virtual visit.

Objective:

PUPs B-LONG aimed to evaluate the safety and efficacy of recombinant factor IX Fc fusion protein (rFIXFc) for prevention and treatment of bleeds in previously untreated patients (PUPs) with hemophilia B.

Methods:

In this open-label, multicenter, multinational, Phase 3 study (NCT02234310), male PUPs aged <18 years with hemophilia B (≤2 IU/dL endogenous FIX) were to receive prophylaxis with rFIXFc. Investigators could treat patients episodically before initiating prophylaxis. Primary endpoint was occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR) and assessment of response to treatment of bleeding episodes with rFIXFc.

Summary:

Of 33 patients enrolled, 26 (79%) were <1 year old, 6 (18.2%) had a known family history of inhibitors, 28 (84.8%) received prophylaxis (17 [51.5%] switched from episodic treatment), and 5 (15.2%) received episodic treatment only. Twenty-seven (81.8%) patients completed the study. Twenty-one (63.6%), 26 (78.8%), and 28 (84.8%) patients had ≥50, ≥20, and ≥10 exposure days (EDs) to rFIXFc during the study, respectively. One patient on prophylaxis developed a low-titer inhibitor (<5.00 BU/mL) after 11 EDs; rate of inhibitor development was 3.0% (1/33 patients). Twenty-three (69.7%) patients had 58 treatment-emergent serious adverse events (TESAEs); 2 were assessed as treatment related (FIX inhibition and hypersensitivity in 1 patient, resulting in withdrawal). Median ABR (prophylaxis) was 1.2 (Table 1). Median number of rFIXFc infusions required to resolve a bleeding episode was 1 (Table 1). For infusions with an evaluation, subjects’ assessment of response to bleeding episode treatment was rated as excellent/good for 22/22 (100%) infusions in the episodic treatment group and 50/57 (87.7%) infusions in the prophylaxis treatment group.

Conclusions:

The study population was representative of PUPs with hemophilia B. Prophylaxis and treatment of bleeding episodes with rFIXFc were effective and generally well tolerated, without unanticipated safety findings. Type and incidence of TESAEs were similar to those expected for the pediatric hemophilia population.