The promise and challenges of bioengineered recombinant clotting factors

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72636/1/j.1538-7836.2005.01367.x.pd

Gene therapy for hemophilia

Individuals with the inherited bleeding disorder hemophilia have achieved tremendous advances in clinical outcomes through widespread implementation of prophylactic replacement with safe and efficacious factor VIII and IX. However, despite this therapeutic approach, bleeds still occur, some with serious consequence, joint disease has not been eradicated, and patients have not yet been liberated from the need for regular intravenous infusions. The shift from protein replacement to gene replacement is offering great hope to achieve durable levels of plasma factor activity levels high enough to remove the risk for recurrent joint bleeding. For the first time, clinical trial results are showing promise for “curative” correction of the bleeding phenotype.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141277/1/pbc26865.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141277/2/pbc26865_am.pd

Implications of emerging pathogens in the management of haemophilia

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72878/1/j.1365-2516.2006.01193.x.pd

New treatment paradigm for hemophilia poses challenges for legacy bioassays

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151338/1/jth14550_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151338/2/jth14550.pd

Strategies towards a longer acting factor VIII

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74903/1/j.1365-2516.2006.01260.x.pd

Not in the genotype: can unexplained hemophilia A result from “micro(RNA) management”?

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154344/1/trf15668_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154344/2/trf15668.pd

The role of telemedicine in the delivery of health care in the COVID‐19 pandemic

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162731/2/hae14044.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162731/1/hae14044_am.pd

New high-technology products for the treatment of haemophilia

This review will focus on new technologies in development that promise to lead to further advances in haemophilia therapeutics. There has been continued interest in the bioengineering of recombinant factor VIII (rFVIII) and factor IX (rFIX) with improved function to overcome some of the limitations in current treatment, the high costs of therapy and to increase availability to a broader world haemophilia population. Bioengineered forms of rFVIII, rFIX or alternative haemostatic molecules may ultimately have an impact on improving the efficacy of therapeutic strategies for the haemophilias by improving biosynthesis and secretion, functional activity, half-life and immunogenicity. Preventing and suppressing inhibitors to factor (F) VIII remain a challenge for both clinicians and scientists. Recent experiments have shown that it is possible to obtain anti-idiotypic antibodies with a number of desirable properties: (i) strong binding avidity to FVIII inhibitors; (ii) neutralization of inhibitory activity both in vitro and in vivo ; (iii) cross-reactivity with antibodies from unrelated patients, and (iv) no interference with FVIII function. An alternative, although complementary approach, makes use of peptides derived from filamentous-phage random libraries. Mimotopes of FVIII can be obtained, which bind to the paratope of inhibitory activity and neutralize their activity both in vitro and in vivo . In this paper, we review advanced genetic strategies for haemophilia therapy. Until recently the traditional concept for gene transfer of inherited and acquired haematological diseases has been focused on how best to obtain stable insertion of a cDNA into a target-cell genome, allowing expression of a therapeutic protein. However, as gene-transfer vector systems continue to improve, the requirement for regulated gene transcription and hence regulated protein expression will become more critical. Inappropriate protein expression levels or expression of transferred cDNAs in non-intended cell types or tissues may lead to target-cell toxicity or activation of unwanted host immune responses. Regulated protein expression requires that the transferred gene be transferred with its own regulatory cassette that allows for gene transcription and translation approaching that of the normal gene in its endogenous context. New molecular techniques, in particular the use of RNA molecules, now allow for transcription of corrective genes that mimic the normal state.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75577/1/j.1365-2516.2004.00996.x.pd

International workshop on immune tolerance induction: consensus recommendations 1

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73382/1/j.1365-2516.2007.01497.x.pd

Anti- factor IIa (FIIa) heparin assay for patients on direct factor Xa (FXa) inhibitors

BackgroundDirect factor Xa (FXa) inhibitors are increasingly prescribed for outpatients, and those transitioning to unfractionated heparin (UFH) for hospital admission are monitored via an anti- FXa assay. Because of assay interference, UFH results would often be critically elevated, confounding dosing.ObjectivesAn anti- factor IIa (FIIa) UFH assay was evaluated for clinical use.MethodsThe BIOPHEN ANTI- IIa (Aniara Diagnostica) assay and anti- FXa INNOVANCE Heparin assay (Siemens Healthcare Diagnostics Products GmbH) were compared on the Siemens BCS XP system. Samples included UFH controls and calibrators and specimens from patients transitioning from apixaban or rivaroxaban to UFH. Method comparison, linearity, recovery, precision, and interference by direct FXa inhibitors were evaluated. The effect of the BIOPHEN ANTI- IIa assay on the rate of critically high UFH results was retrospectively reviewed 4 months after implementation.ResultsAccuracy studies using 0.24 and 0.50 IU/mL UFH yielded means and standard deviations of 0.26 ± 0.01 and 0.58 ± 0.01 IU/mL, respectively. Within- run and between- run coefficients of variation were 4.6% and 15.5% for the low control, and 1.8% and 10.6% for the high control. The method comparison slope was 0.9965 (r2 = 0.9468). The linear range was 0.1 to 1.3 IU/mL. The assay measured UFH in the presence of 192 ng/mL apixaban or 158 ng/mL rivaroxaban. Introduction of the assay for clinical use reduced the monthly percentage of critically high results from 9.4% to 3.8% for admitted heparinized patients who recently discontinued apixaban or rivaroxaban.ConclusionsThe BIOPHEN ANTI- IIa assay is suitable for patients transitioning off apixaban or rivaroxaban.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156142/2/jth14806.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156142/1/jth14806_am.pd