The goal of Dr. Chen's research is to examine a method for selectively expanding hematopoietic stem cells expressing the factor VIII transgene. She will also examine the immune consequences of this approach, based on the idea that gene transfer in platelets evades immune recognition. This research has the potential to elicit important clues to developing an approach for gene therapy of hemophilia A and hemophilia A with inhibitors.
Dr. Chen earned a PhD in hematology from Fujian Medical University in China. She already has more than 27 papers published in the Chinese medical literature. Her research in hemophilia and gene therapy will be under the mentorship of Dr. Qizhen Shi, MD, PhD, Associate Investigator at the Blood Research Institute and Assistant Professor of Pediatric Hematology at the Medical College of Wisconsin.
Objective:
Age is a major risk factor for cardiovascular disease. Comprehensive care and the improved safety of factor replacement therapy and therapeutic approaches, such as prophylaxis, have increased life expectancy for people with hemophilia people with hemophilia (PwH).
PwH may acquire cardiovascular risk factors (such as diabetes, hypertension, hyperlipidemia, obesity and renal disease) as a consequence of advancing age, lifestyle and hemophilia- related conditions, yet little information is available on cardiovascular risk assessment among PWH.
The ADVANCE Working Group, an expert panel of European hemophilia centers supported by an educational grant from Bayer Healthcare, convened to raise awareness of age-related comorbidities among PwH. There are currently no evidence-based guidelines for antithrombotic management in PwH presenting with acute coronary syndrome (ACS). ADVANCE met to perform a review of the current European Society of Cardiology guidelines, and to consider how best they should be adapted for PWH.
Methods:
Structured communication techniques based on a Delphi-like methodology were used to achieve expert consensus on key aspects of clinical management.
Summary:
The main final statements are: a) ACS and myocardial revascularization should be managed promptly by a multidisciplinary team that includes a hemophilia expert; b) Each comprehensive care center for adult PwH should have a link to a cardiology centre with an emergency unit and 24 hour availability of PCI; c) PCI should be performed as soon as possible under adequate clotting factor protection; d) Bare metal stents are preferred to drug eluting stents; e) Anticoagulants should only be used in PwH after replacement therapy; f) Minimum trough levels should not fall below 5-15% in PwH on dual antiplatelet therapy; g) The duration of dual antiplatelet therapy after ACS and PCI should be limited to a minimum; h) PwH receiving antiplatelet therapy should be offered gastric protection; i) The use of GPIIb- IIIa inhibitors is not recommended in PwH other than in exceptional circumstances; j) The use of fibrinolysis may be justified in PwH when primary PCI (within 90 minutes) is not available ideally under adequate clotting factor management.
Conclusion:
It is hoped that the results of this initiative will help to guide optimal management of ACS in PwH.
Objective:
To assess subjective and objective outcomes of total joint arthroplasty (TJA) as a treatment for hemophilic arthropathy, and to assess the safety and efficacy of perioperative pharmacologic thromboprophylaxis as a means to prevent venous thromboembolism in this population.
Methods:
We performed a retrospective chart review to identify patients with congenital bleeding disorders who underwent TJA between 1987 and 2012. We collected data on range of motion (ROM) and pain before and after surgery and on early and late complications (bleeding, infection, thrombosis). Data are presented descriptively using median values and ranges where appropriate.
Summary:
We identified 38 procedures (29 knees (TKA) and 9 hips (THA) in 28 patients (26 male, 2 female) with hemophilia A (n = 21), hemophilia B (n = 4), factor 11 deficiency (n = 1) and von Willebrand disease (n = 2). Median age at operation was 42 years (range, 17 – 74) for TKA and 45 years (range, 18 – 71) for THA. Inhibitors were present in one patient with hemophilia A (1.5 B.U.) and one patient with factor 11 deficiency (0.5 B.U.). All patients were treated with hemostatic agents appropriate to their disorders for up to 4 to 6 weeks post- operatively. Complete data at 2 months post-operatively are available for 27 TKA patients, of whom, 7 (23%), demonstrated improvement in ROM (median 15 degrees, range 5 - 25). At 1.5 years post-operatively, 17/29 (59%) TKA patients showed improvement in ROM (median 15 degrees, range 4 - 58) and 100% reported decreased knee pain. All 9 THA patients demonstrated improved ROM at 2 months post-operatively. Eight (89%) demonstrated gains in internal rotation (median, 45 degrees, range 15 – 45), 9 (100%) in external rotation (median 30 degrees, range 15 – 45), 5 (56%) in flexion (median 35 degrees, range 27 – 55), 7 (78%) in extension (median 15 degrees, range 3 – 95), and 7 (78%) in abduction (median 15 degrees, range 10 – 25).
We were able to contact 22 of 28 study subjects (79%), accounting for 31 of 38 (82%) procedures. Patients who underwent 25 of the 29 TKAs (86%) and 6 of the 9 THAs (67%) agreed to provide answers to yes/no questions about their experience with TJA. 25 of 25 (100%) TKA subjects reported improvement in pain and stated that if given the opportunity to go back and revisit their decision, would make the same decision to have the surgery. 24 of 25 (96%) TKA subjects reported improvement in their joint function after the surgery. 6 of the 6 THA subjects we contacted stated that they experienced improvement in joint pain and function as a result of the surgery, and 5 of 6 (83%) stated that they would choose to have the surgery if they had to choose again.
Low molecular weight heparin was administered post-operatively in 29 of 38 procedures (76%). Thromboprophylaxis was discontinued in 3 patients for non-joint bleeding (one hematuria, two cases of hypotension and anemia). There were no symptomatic VTE. Early complications included 5 cases of cellulitis and 2 hemarthroses in patients not receiving thromboprophylaxis. Late complications included two patients with aseptic loosening in prosthetic knees leading to TKA revisions, one with a subsequent joint infection requiring surgical debridement and one patient with a worsening flexion contracture requiring TKA revision.
Conclusions:
While there are risks associated with TJA in patients with bleeding disorders, our data suggest they are outweighed by the benefits manifesting as decreased pain and improved function. Pharmacologic thromboprophylaxis appears safe in this population; whether it is necessary is unknown and should be a subject of future trials.
Objective:
The binding behavior of rVIII-SingleChain to plasma-derived von Willebrand Factor (pdVWF) was assessed in surface plasmon resonance (SPR) studies.
Methods:
The purification of VWF from human plasma–yielded pdVWF free of factor VIII (FVIII). Subsequently, isolated pdVWF was immobilized on a SPR gold chip using monoclonal antibodies (MAbs). Thereafter, the binding behavior of rVIII-SingleChain and full-length rFVIII molecules were studied and binding kinetics were calculated. Regeneration of pd-VWF was performed with calcium chloride, while regeneration of the covalently coupled anti-VWF MAbs was achieved in the presence of an acidic pH.
Summary:
The affinity of CSL Behring’s rVIII-SingleChain to pdVWF was significantly higher than those of commercially available rFVIII full-length molecules. The higher affinity was derived from a higher association rate constant, while the dissociation rate constants were comparable. Intriguingly, the higher affinity had no influence on other functional characteristics of rVIII-SingleChain (eg, the binding to phospholipids, thrombin generation capacity, and FVIII enzymatic activity were comparable to full-length rFVIII). The results obtained from the SPR studies in vitro appear consistent with the observation of improved pharmacokinetic characteristics for rVIII-SingleChain in comparison to full-length rFVIII. After treatment of hemophilia A mice with single doses of rVIII-SingleChain or full-length rFVIII, the systemic availability and mean residence time were found to be increased for rVIII- SingleChain compared to full-length rFVIII. In addition, a decreased clearance rate and an enhanced terminal half-life were observed for rVIII-SingleChain, while in vivo recovery and volume of distribution of rVIII-SingleChain were comparable to full-length rFVIII.
Conclusion:
Overall, it seems conceivable that the higher affinity of CSLB’s rVIII-SingleChain to pdVWF may have a positive effect on its systemic availability by a delayed elimination from plasma.
