Managing Severe Hemophilia A in Children: Pharmacotherapeutic Options

Abstract

Hemophilia A is the most common severe inherited bleeding disorder in males. Initial treatment strategies focused on the use of factor concentrates to prevent joint bleeding and the development of long-term crippling arthropathy. The current standard of care has evolved from regular replacement of factor VIII concentrates which has significantly improved the quality of life for those with severe disease to include and consider novel therapies that augment or bypass the hemostatic pathway (ie, emicizumab, Mim8). Other pipeline therapies that suppress specific natural anticoagulant pathways (ie, antithrombin, TFPI) to reestablish hemostatic balance are under Phase 3 trial investigation. These novel therapeutics have allowed providers more variety in dosing regimens and ease of administration while also maintaining effective bleeding prevention. The possibility of “curative” gene therapy is under exploration, with ongoing clinical trials in adult males.

Keywords:

• factor VIII
• therapeutic management
• coagulation
• pediatrics

Abbreviations

AAV, adeno-associated viral; ABR, annualized bleeding rate; BPA, bypassing agent; EHL, extended half-life; F, clotting factor; Fc, crystallizable fragment; HSCT, hematopoietic stem cell transplant; HA, hemophilia A; HIV, human immunodeficiency virus; ITI, immune tolerance induction; PK, pharmacokinetic; siRNA, small interfering ribonucleic acid; SHL, standard half-life; TFPI, tissue factor pathway inhibitor; TMA, thrombotic microangiopathy; VWF, von Willebrand factor.

Author contributions

KR wrote and edited the manuscript. RFS and MUC reviewed, edited and contributed to the manuscript.

Disclosure

KR received a 2020 HTRS/Novo Nordisk Clinical Fellowship Award in Hemophilia and Rare Bleeding Disorders from the Hemostasis and Thrombosis Research Society (HTRS), which was supported by an educational grant from Novo Nordisk Inc. MUC has received honoraria from Sanofi, Genentech/Roche, Kedrion, Catalyst Biosciences, Hema Biologics, Takeda, Pfizer, Bayer, Novo Nordisk, Octapharma, Spark, BioMarin, Uniqure, Global Blood Therapeutics, Chiesi. MUC is employed by Agios Pharmaceuticals. RS has received honoraria from Sobi/Sanofi, Genentech/Roche, Grifols, Sigilon, Hema Biologics, Takeda, Pfizer, Bayer, Catalyst, Guardian Therapeutics, Novo Nordisk, Octapharma. RS has investigator initiated grant funding from Takeda (ATHN 9 and SAFE study), Genentech/Octapharma (Emi PUPs and Nuwiq ITI) and Octapharma (MOTIVATE study). The authors report no other conflicts of interest in this work.