Abstract Ref Number = APCP29
The new era in diagnosis and management of old blood diseases
Godfrey ChiFung CHAN
Department of Paediatrics Adolescent Medicine, Queen Mary Hospital HKUShenzhen Hospital, The University of Hong Kong, Stem Cells Regenerative Medicine Consortium, The University of Hong Kong
Hemophilia and other inherited bleeding disorders are diagnosed by a panel of function tests plus specific factors assays. However, relative sophisticated tests are not routinely available in most service laboratories of Asia. In recent years, genetic tests have made a significant impact on the diagnostic approach for bleeding disorders due to its easier accessibility for both public and private hospitals. Panel NGS, WES or WGS are readily available now at a reasonable price. The diagnostic algorithm may have to be modified to include the genetic information. However, one has to be careful about genetic variants with unknown significance which may mislead both the clinicians and patients’ families. On the other hand, with the advances in molecular biology and bio-engineering, the management of bleeding disorders progresses rapidly.
Coagulation factors can be manufactured by recombinant molecular technology and the recent advance is to add bio-compatible materials to the recombinant factors so their half-life can be prolonged. These enhanced half-life coagulation factors include factors attached to immunoglobulin Fc fragment, peg-glycosylated particle, or albumin. However for FVIII, the efficacy of these strategies is affected by the vWF which naturally stabilize the factor VIII within our body. The latest advance is to modify the vWF binding domains of the FVIII so its half-life can be prolonged further. On the other hand, the use of by-passing agent to overcome the barrier of factor inhibitor also emerged.
One of the most notable successes is the development of bispecific antibody linking FIX to FX directly even without FVIII. Clinical trial of this approach is quite promising and it has been approved by the FDA for hemophilia A patients with inhibitor recently. Other advantages of this treatment are subcutaneous administration and prolonged action which can last up to 1 to 4weeks. But it may not be potent enough to cover major operation and the risk of thromboembolism remains to be observed.
The other options include Anti-TFPI, RNA silencing agent, etc. but they are still in the phase of early clinical trials. Finally, for both FVIII and FIX, gene therapy is already clinically feasible now. The current approach of direct infusing gene vectors (i.e. AAV) intravenously seems to be safe and helpful for patients >12-year-old. How to achieve durable expression and avoid insertional mutagenesis remains a challenging task. Due to the high cost of all these advanced therapeutics, how they can benefit majority of patients in Asia with suboptimal financial status requires the concerted efforts from the medical professionals, charity organizations, drug companies and also Governments in solving the related problems.