Current therapeutic approaches in the management of hemophilia-a consensus view by the Romanian Society of Hematology

Abstract

Hemophilia A (HA) and hemophilia B (HB) are rare disorders, being caused by the total lack or under-expression of two factors from the coagulation cascade coded by genes of the X chromosome. Thus, in hemophilic patients, the blood does not clot properly. This results in spontaneous bleeding episodes after an injury or surgical intervention. A patient-centered regimen is considered optimal. Age, pharmacokinetics, bleeding phenotype, joint status, adherence, physical activity, personal goals are all factors that should be considered when individualizing therapy. In the past 10 years, many innovations in the diagnostic and treatment options were presented as being either approved or in development, thus helping clinicians to improve the standard-of-care for patients with hemophilia. Recombinant factors still remain the standard of care in hemophilia, however they pose a challenge to treatment adherence because they have short half-life, which where the extended half-life (EHL) factors come with the solution, increasing the half-life to 96 hours. Gene therapies have a promising future with proven beneficial effects in clinical trials. We present and critically analyze in the current manuscript the pros and cons of all the major discoveries in the diagnosis and treatment of HA and HB, as well as identify key areas of hemophilia research where improvements are needed.

Keywords: Hemophilia; Romanian Society of Hematology; consensus view; diagnosis and management.

Figure 1

This cascade is initiated by the exposure of the extravascular protein Tissue Factor (TF) to blood, allowing the formation of the TF-factor VIIa (FVIIa) complex. This complex is able to activate small amounts of FIXa and FXa before it is rapidly inhibited by TF pathway inhibitor (TFPI). FXa promotes the generation of thrombin. Although no sufficient amounts of thrombin are produced to allow fibrin formation, thrombin amplifies its own production by inducing a positive feedback loop via activation of FXI and the protein cofactors FV and FVIII. This feedback activation is crucial for the formation of the FIXa/FVIIIa complex (also known as the tenase complex), which is needed to generate adequate amounts of FXa and thrombin to permit fibrin formation. Now, it is known that the contact pathway (or intrinsic pathway) is not needed for normal hemostasis in vivo.

Figure 2

Genetic testing can be done at different timepoint in conception.

Figure 3

The cascade of events leading to hemophilic arthropathy. A. The acute bleeding in the joint space, results first in B. synovitis, which is followed by C. destruction of articular cartilage, which ultimately results in permanent D. joint deformity. Secondly, A. Acute bleeding causes E. Joint capsule distension, a condition which can also be the result of synovitis. The E. Joint capsule distension is followed by F. reflex muscle inhibition and G. Extensor muscle atrophy. All of these events ultimately lead to the H. Loss of mobility in the respective joint, which causes even more frequent episodes of acute bleedings.

Figure 4

Chronic synovitis (left) and articular cartilage destruction (right) seen in a 25-year-old patient with hemophilic arthropathy.