Hemophilia A in Women - Key Points to Discuss With Your Patients

Comprehensive discussions with female patients about hemophilia A, including its inheritance pattern, diagnosis, management of bleeding symptoms, and family planning, can lead to more informed healthcare decisions and proactive symptom management.

Diagnosing Hemophilia A in Women

As for naming conventions, the International Society on Thrombosis and Haemostasis (ISTH) suggests using the term “symptomatic carrier” for women and girls with an abnormal hemophilia gene who exhibit bleeding symptoms and have clotting factor levels of at least 40%. For those with the same genetic and clotting factor profile, but without bleeding symptoms, “asymptomatic carrier” is the most appropriate term to use.

Women and girls with an abnormal hemophilia gene and clotting factor levels below 40% have hemophilia, and based on their baseline clotting factor levels, they can be categorized as having mild (≥5% to <40%), moderate (≥1% to <5%), or severe (<1% of normal factor VIII levels) hemophilia.

While a detailed medical history and physical examination can check for signs of hemophilia like bruising or hemarthrosis, a definitive diagnosis requires blood tests. In particular, a factor activity assay is needed to measure factor VIII levels and determine the severity of the disorder. Genetic testing can also be used to further confirm the diagnosis and provide specific information about the specific mutation, such as risk of inhibitors.

Discussing Hemophilia Genotypes in Women

Describing the basic genetics of hemophilia A to female patients can help them understand why they might show fewer symptoms than men. This can include discussing inheritance patterns and genotypes.

Inheritance Patterns of Hemophilia A

Hemophilia A predominantly affects men due to its X-linked recessive inheritance pattern. A simple explanation for patients is that men possess one X chromosome (XY), and if their only X chromosome carries the mutation, they will express the condition. Women, on the other hand, have 2 X chromosomes (XX) and therefore may or may not exhibit symptoms.

Different Hemophilia Genotypes in Women

In the context of hemophilia in women, there are 2 different genotypes, heterozygous and homozygous:

Heterozygous female genotype refers to a situation where a woman carries one defective gene but still has another X chromosome with a healthy copy. This can reduce the severity of symptoms.

Homozygous female genotype refers to a more rare situation where a woman has either inherited two X chromosomes with the hemophilia gene, or has inherited one affected X chromosome and another with a nonfunctional mutation or deletion. Unlike women with a heterozygous genotype, women with a homozygous genotype do not have a functioning X chromosome that can serve as a backup, which is why they tend to have more severe symptoms.

That said, both female hemophilia genotypes can result in bleeding symptoms and carry the risk of transmitting the hemophilia gene to their offspring.

Hemophilia Symptoms in Women

Discussing symptoms of hemophilia A with female patients can begin with an explanation of how a deficiency or dysfunction of coagulation factor VIII results in difficulties in clotting and an increased risk of bleeding. This can lead to common signs and symptoms of hemophilia like excessive bleeding, easy bruising, muscle swelling and pain, and blood in the urine or stool.

Women with hemophilia and symptomatic carriers can also face additional sex-specific symptoms, such as heavy or prolonged menstrual bleeding, and bleeding during pregnancy or after childbirth.

Hemophilia A Risk Factors in Women

These additional symptoms in women and girls with hemophilia can lead to complications that patients should be aware of. It is also important to discuss proactive and preventive measures that can help manage these complications.

Female Hemophilia and Menstruation

Heavy menstrual bleeding (HMB), or menorrhagia, is a common symptom in women and girls with hemophilia. HMB can impact not just their physical well-being, but can also negatively affect their social and emotional quality of life. Indicators of abnormal menstrual bleeding can include menstrual episodes lasting 8 or more days, nighttime overflow, and formation of large menstrual fluid clots.

The National Bleeding Disorder Foundation’s Medical and Scientific Advisory Council (MASAC) recommends that HMB should be managed through a multidisciplinary approach, often requiring multiple concurrent therapies to achieve treatment goals, such as hormonal therapies alongside antifibrinolytics. Hemophilia A patients with menorrhagia should also be frequently evaluated for iron deficiency and offered supplementation therapy if ferritin levels are low, even in cases where hemoglobin levels fall within the normal range.

Pregnancy in Women With Hemophilia

Pregnancy requires special care and management in women with hemophilia and symptomatic carriers. Your patients need to be made aware of the following:

Changing factor VIII levels: Factor VIII levels naturally rise during pregnancy, which may temporarily reduce bleeding risk.

Bleeding risks: Factor VIII levels drop again after delivery, resulting in an increased risk of significant bleeding following childbirth. This can include prolonged bleeding from the birth canal, a condition known as postpartum hemorrhage. It’s worth noting that surgical procedures can also cause complications, meaning delivery by cesarean section also comes with bleeding risks.

Delivery plan: In addition to managing bleeding risks, a delivery plan can minimize the risk of injury to the newborn in the case of hemophilia inheritance. Specific safety protocols, such as avoiding the use of forceps or vacuum extractors during delivery whenever possible, should be discussed in advance.

Family Planning for Hemophilia A in Women 

As per MASAC guidelines, all women with bleeding disorders who plan to become pregnant should be offered a preconception genetic consultation and be introduced to the various methods used to diagnose a potentially affected fetus, as well as the associated risks of each method. These methods include preimplantation genetic diagnosis (PGD); prenatal tests such as chorionic villus sampling, amniocentesis, and cordocentesis and ultrasound to determine the sex of the fetus.

Prenatal testing helps determine the necessary precautions for managing potential obstetrical complications during pregnancy and delivery if the child is diagnosed with a bleeding disorder.

Hemophilia Inheritance – Explaining the Potential Risk to Children

A clear understanding of hemophilia inheritance can also help patients with their family planning. While men have a higher risk of developing severe hemophilia A, women can also experience significant bleeding issues, particularly if they have skewed X-inactivation or are compound heterozygous for factor gene variants.

Hemophilia A Treatment Options

MASAC guidelines state that anyone with an inherited bleeding disorder should have access to suitable evidence-based treatment choices. Depending on the needs of the patient, they may benefit from either episodic care, treating in response to a bleeding episode, or prophylactic care, regular scheduled treatments to prevent bleeding episodes in the first place. Available treatment options can include the following:

Recombinant factor VIII concentrates (rFVIII): This is administered intravenously to prevent or control bleeding episodes. Third-generation rFVIII products are created through advanced genetic engineering techniques without using human or animal proteins in their final formulation, meaning the risk of human viral contamination is very low. Note that rFVIII products with an extended half-life are now available, allowing for less frequent infusions while maintaining effective clotting support.

Plasma-derived factor VIII concentrates: Recent versions have benefited from improved viral-depleting processes and donor screening practices that have significantly reduced the risk of viral transmission, although a slight possibility of viral transmission remains. MASAC recommends considering plasma-derived factor VIII with von Willebrand Factor (vWF) infusions for newly diagnosed patients or when additional vWF support is needed.

Non-factor therapies: These are designed to treat hemophilia without replacing the missing clotting factor and include factor mimetic and rebalancing agents. Both classes of treatment are administered via subcutaneous injection.

Factor mimetic therapy is a bispecific monoclonal antibody that binds to factor IX/IXa and factor X/Xa, to mimic the function of factor VIII. In contrast, anti-TFPI rebalancing agent is a monoclonal antibody that inhibits tissue factor pathway inhibitor (TFPI) through its K2 domain, reducing FXa inhibition and promoting thrombin generation to facilitate clot formation.

Learn about the risk of inhibitors in hemophilia A treatment for both previously treated patients and those newly exposed to factor VIII therapies

Antifibrinolytic drugs: These medications, taken orally as a tablet or liquid, prevent the breakdown of blood clots. In women with HMB, they can be offered alongside hormonal treatments. MASAC recommends that a dose of clotting factor be taken first to form a clot, then aminocaproic acid, to preserve the clot and keep it from being broken down prematurely.

Synthetic hormone therapy: Some patients with mild hemophilia A may benefit from a synthetic hormone via injection or intranasal spray that can temporarily boost the body's own factor VIII levels. This approach is typically used for minor bleeding episodes or before minor surgical procedures, but should be administered cautiously in pregnant women during labor and childbirth.

Gene therapies: This therapy involves a single intravenous infusion designed to help the body produce its own factor VIII by transferring a functional gene. Gene therapy is approved for use in adults with severe hemophilia A who have been screened first for specific antibodies and have been evaluated as having a well-functioning liver.

Improving Care for Hemophilia A in Women

By creating an open and supportive environment for female patients and thoroughly discussing relevant key considerations with them, these patients can then have a comprehensive understanding of their condition and seek appropriate treatment options.

How lower factor VIII levels put your patients at greater risk of bleeds