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Ferrata Storti Foundation
Haematologica 2019 Volume 104(9):1702-1709
Hemophilia A and B: molecular and clinical similarities and differences
Giancarlo Castaman1 and Davide Matino2
1Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence, Italy and 2Department of Medicine, McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
Introduction
Hemophilia A and B are rare X-linked bleeding disorders caused by mutations in the genes encoding coagulation factor VIII (FVIII) and factor IX (FIX). Hemophilia A (HA) is more common than hemophilia B (HB), with a prevalence of one in 5,000 male live births compared to one in 30,000, respectively.1
The disease severity in hemophilia is classified according to the plasma level of FVIII or FIX activity. The severe form is defined as a factor level <1% of normal, the moderate form as a factor level of 1-5%, and the mild form with a factor level >5 and <40%.2 Patients with severe hemophilia frequently develop hemorrhages into joints, muscles or soft tissues without any apparent cause. They can also suffer from life-threatening bleeding episodes such as intracranial hemorrhages. Persons with mild and moderate factor deficiency rarely experience spontaneous hemor- rhages, and excessive bleeding mostly occurs only following trauma or in associa- tion with invasive procedures.
The residual factor activity generally correlates well with clinical characteristics; however, heterogeneous bleeding phenotypes among individuals with the same factor levels can occur.3 Furthermore, although HA and HB have been usually con- sidered clinically indistinguishable with negligible differences in severity and out- comes, several recent studies are challenging this concept, suggesting that patients with HB could have a less severe bleeding tendency compared to HA patients with the same residual plasma level.4
In this review, we provide an up-to-date summary of evidence highlighting the similarities and differences of these two clotting factor deficiencies.
Comparison of gene defects in hemophilia A and hemophilia B
Both F8 and F9 genes are located on the X chromosome, F8 gene being at the end of the long arm at Xq285and F9 IX gene on the long arm, more towards the cen- tromere, at Xq27.6
F8 gene is extremely large (approx.180 kb) and structurally complex (26 exons), while F9 gene is considerably smaller (approx. 34 kb in length) and structurally sim- pler, containing only eight exons, the largest of which is only 1,935 bp long.
The mutations causing hemophilia A and B have been characterized in several thousands of patients. What is immediately evident from the enormous number of mutations that have been elucidated is that the molecular basis of the hemophilias is extremely diverse.
Point mutations, deletions, insertions, and rearrangements/inversions have all been found either in F8 and F9 genes. However, the relative frequency of these mutations differs between HA and HB. In particular, gross genetic abnormalities account for approximately 7% of HB cases in contrast to HA in which gene rearrangements account for almost half of severe cases, with intron 22 inversion being the most common defect. A summary of the differential characteristics of hemophilia A and B is presented in Figure 1.
Previous studies have shown that the mutation type in the FVIII and FIX genes correlates with the residual factor activity in plasma and the bleeding tendency in hemophilia patients, with larger gene defects generally associated with a more severe clinical phenotype.3,7 Although one could intuitively argue that HA and HB patients with null mutations could experience a similar bleeding history, such a comparison has never been systematically carried out.
The different prevalence of mutations predicting a null allele also explains a high- er proportion of HB patients that can be classified as cross-reacting material posi- tive (CRM+). The presence of null mutations prevents the synthesis of any detectable FVIII or FIX antigen. Approximately 5% of HA patients are CRM+ and
Correspondence:
GIANCARLO CASTAMAN
giancarlo.castaman@unifi.it
Received: March 5, 2019. Accepted: June 5, 2019. Pre-published: August 8, 2019.
doi:10.3324/haematol.2019.221093
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/9/1702
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