Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Mar;27(2):e164-e179.
doi: 10.1111/hae.14186. Epub 2020 Dec 13.

Genetic causes of haemophilia in women and girls

Connie H Miller  1 , Christopher J Bean  1
Affiliations
Review

Genetic causes of haemophilia in women and girls

Connie H Miller et al. Haemophilia. 2021 Mar.

Abstract

Women and girls reported as "haemophilic females" may have complex genetic causes for their haemophilia phenotype. In addition, women and girls may have excessive bleeding requiring treatment simply because they are heterozygous for haemophilia alleles. While severe and moderate haemophilia are rare in females, 16% of patients with mild haemophilia A and almost one-quarter of those with mild haemophilia B seen in U.S. haemophilia treatment centres are women and girls. A phenotypic female with a low level of factor VIII or factor IX may be classified into one of the following categories of causality: homozygosity (two identical haemophilia alleles), compound heterozygosity (two different haemophilia alleles), hemizygosity (one haemophilia allele and no normal allele), heterozygosity (one haemophilia allele and one normal allele), genetic causes other than haemophilia and non-genetic causes. Studies required for classification may include coagulation parameters, F8 or F9 sequencing, F8 inversion testing, multiplex ligation-dependent probe amplification, karyotyping and X chromosome inactivation studies performed on the patient and parents. Women and girls who are homozygous, compound heterozygous or hemizygous clearly have haemophilia, as they do not have a normal allele. Heterozygous women and girls with factor levels below the haemostatic range also meet the definitions used for haemophilia treatment.

Keywords: factor IX; factor VIII; haemophilia A; haemophilia B.

PubMed Disclaimer

Conflict of interest statement

DISCLOSURES

The authors state that they have no interests which might be perceived as posing a conflict or bias. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Figures

FIGURE 1
FIGURE 1
Theoretical distribution of factor VIII or IX levels in women heterozygous for variants causing haemophilia (heterozygotes) and for women not having variants causing haemophilia (controls)
FIGURE 2
FIGURE 2
Comparison of the phenotypes of three haemophilia heterozygotes in a family transmitting haemophilia A, showing factor VIII coagulant activity (FVIII:C), von Willebrand factor antigen (VWF:Ag) and von Willebrand factor activity as ristocetin cofactor (VWF:RC) in units per decilitre
FIGURE 3
FIGURE 3
Odds ratios and 95% confidence intervals of bleeding symptoms in women heterozygous for haemophilia A or B compared to women without haemophilia from three studies: A, B and C
See this image and copyright information in PMC

References

    1. Rosner F Hemophilia in classic rabbinic texts. J Hist Med Allied Sci. 1994;49(2):240–250. - PubMed
    1. Treves F London Hospital. A case of haemophilia; pedigree through five generations. Lancet. 1886;128(3290):533–534.
    1. Merskey C The occurrence of haemophilia in the human female. Q J Med. 1951;20(79):299–312. - PubMed
    1. Douglas AS, Cook IA. Deficiency of antihaemophilic globulin in heterozygous haemophilic females. Lancet. 1957;270(6996):616–619. - PubMed
    1. Haldane JBS. On the rate of spontaneous mutation of a human gene. J Genet. 1935;31:317–326. - PubMed