#144: Fun Facts for Factor VIII (or XI): Managing Hemophilia

June 18, 2025 | By Sam Masur

Audio

Summary:

Dive into hemophilia with three-peat guest Dr. Weyand, the Shematologist! In this episode, we break down the basics of hemophilia A and B, from inheritance and pathophysiology to the latest advancements in diagnosis and treatment. Factor in these practical tips for managing acute bleeding, counseling families, and navigating the complexities of prophylaxis—all while keeping kids safe and active. The pearls just kept flowing and flowing!

Hemophilia Pearls

1. Think about hemophilia in female patients with excessive bruising, bleeding, hemarthroses, or heavy menstrual bleeding, especially if there’s a family history.
2. A normal PTT or lack of bleeding in surgery doesn’t necessarily rule out hemophilia, so consider factor levels if clinically suspicious for hemophilia.
3. Giving factor for a child with hemophilia with a bleed is almost always the best first line.

Hemophilia Notes

What is hemophilia?

Hemophilia is a bleeding disorder caused by a deficiency of a specific clotting protein, known as a clotting factor, which makes the blood unable to clot effectively. Hemophilia A and B are inherited bleeding disorders caused by deficiencies of clotting factor VIII and IX, respectively. Hemophilia C is a rare condition caused by factor XI deficiency. They present as bleeding disorders of varying severity, based on the amount of factor present:

• Normal – factor levels greater than 40-50%
• Mild hemophilia – factor levels between 5% and 40-50%
• Moderate hemophilia – factor levels between 1-5%
• Severe hemophilia – factor levels less than 1%

Most children are diagnosed around 12-18 months of age, as they begin to walk and become more active. 

Some may be diagnosed before birth due to family history, or as infants based on prolonged bleeding after heel puncture, IV placement, or circumcision. Earlier diagnosis typically means severe disease.

What is the inheritance of hemophilia?

Hemophilia is an X-linked disease, meaning males with one abnormal X chromosome are typically affected and females with one abnormal X chromosome are typically carriers. 

The severity and phenotype are based on the specific gene mutation present, which can affect both the amount and function of the factor present.

While males are classically affected, females are also affected more commonly than people realize. Female carriers often have mild hemophilia with higher levels of factor VIII or IX, but can still have significant bleeding.  Females may present in a more heterogeneous manner based on the manner of inheritance. Common mechanisms include lyonization (x-inactivation) of the X chromosome, inheritance of abnormal X-chromosomes from both parents, and Turner Syndrome. Based on hemophilia registries, one out of every three patients with hemophilia is female, though the measured prevalence is much less (only 4.5% of patients).

What are the manifestations of hemophilia?

The most common manifestations of hemophilia are bleeding, both external and internal:

• Easy bruising from small accidents
• Easy bleeding with minor trauma, such as epistaxis (nosebleeds) or bleeding with brushing/flossing teeth
• Hemarthrosis (bleeding into a joint) that can present as pain, immobility, and joint deformity, particularly with recurrent bleeding
• Intramuscular bleeding
• Intracranial hemorrhage, which can be spontaneous and is associated with high morbidity and mortality

How does a hematologist explain hemophilia to parents?

Hemophilia is when the body is missing a protein that helps the blood to clot. Blood clots are important to stop bleeding when there is an injury to the vessel, so a missing clotting factor can lead to bleeding. It is a condition that can be managed by supplementing the missing clotting factor, which can help patients avoid most of the manifestations and complications of hemophilia.

Pearl: Due to heritability, many patients have dealt with hemophilia in the family. There is a tight-knit community, so many families may know a great deal about hemophilia.

What about the coagulation cascade?

The coagulation cascade is the system through which blood clots form, and is more complicated than the version we learned in med school! Hemophilia affects the intrinsic pathway, which includes factors XII, XI, IX, and VIII. 

What is the diagnostic workup for hemophilia?

• • Clot based assays, prothrombin time and partial thromboplastin time (PT and aPTT), are good first-line tests. aPTT will be prolonged in hemophilia. PT evaluates the extrinsic pathway and will be normal, as it evaluates factor VII. The most common cause of prolonged PTT in an otherwise healthy child is transient lupus anticoagulant, which is not clinically significant. Normal aPTT does not rule out mild hemophilia.

• Factor VIII and IX levels provide a more definitive idea of the likelihood of hemophilia. Limitations for factor levels include elevation in the setting of inflammation, consumption of factors in disseminated intravascular coagulation (DIC), decreased production in liver disease, and differences in reference values for neonates.

• Genetic testing should be considered in patients with family history, unclear diagnosis, or to determine carrier status.
• Consider also chromogenic assays, von Willebrand Factor (vWF) assay, factor XI, factor XIII to evaluate other etiologies for bleeding.
• Consider head ultrasound in neonate with a history or findings concerning for bleeding disorder to screen for intracranial hemorrhage.

Children born to mothers with hemophilia should be evaluated via cord blood testing for factor VIII and IX levels.

Prolonged bleeding time after heel puncture is difficult to assess, but Dr. Weyand’s expert opinion is to trust experienced nurses who have performed many heel punctures if they feel it is prolonged.

What about treatment?

Which children should receive prophylaxis?

Prophylaxis is always indicated for children with severe hemophilia, but also for children with mild and moderate disease based on their bleeding phenotype. It is typically begun around the first birthday, as the risk of bleeding increases as children become more mobile. Children with severe disease who require earlier therapy may require a port for central access, which has its own associated risks. While prophylaxis may be beneficial for some children with mild or moderate disease before their first birthday, the risk/benefit typically doesn’t favor treating at that age.

What is the goal of prophylactic therapy?

The goal of prophylactic therapy, historically, was to keep trough factor levels above 1% and prevent severe bleeding, given the frequency of infusions to maintain higher trough levels. With better products available, the goal may now be higher. 

What treatment is available?

Factor VIII and IX replacement are available as intravenous infusions. Parents typically perform these infusions at home, though many children learn how to do their own venipuncture over time.

For factor VIII, 1 unit/kg will typically increase factor level by 2%. Therefore, 50 units/kg will typically get a patient to 100%. Factor levels above 100% may present thrombosis risk in adults. Per Dr. Weyand’s expert opinion, this risk isn’t as great in children as they don’t often have other thrombotic risk factors.

Factor VIII has a half life of 8-12 hours, therefore it requires infusions at least three times per week. 

Factor IX is dosed at 100 units/kg and does not bind vWF, so it has a longer half-life. Long acting factor IX products allow for infusions at up to two week intervals. 

Pearl: Children clear factor more rapidly than adults, so they typically require more frequent dosing.

Efanescotog alfa is a recombinant factor VIII product that does not bind the patient’s endogenous vWF, therefore has a longer half-life and only requires weekly infusions. 

Emicizumab is a bi-specific monoclonal antibody, meaning it has two binding domains. It performs the function of factor VIII, binding activated factor IX and factor X, facilitating the activation of factor X into factor Xa. It is administered in a subcutaneous injection, dosed every 1-4 weeks. It should be considered in infants who might not typically receive IV factor infusions to prevent the small but devastating risk of intracranial hemorrhage. It has the benefit of providing steady-state hemostasis without the peaks and troughs seen with factor replacement.

Marstacimab is a monoclonal antibody against tissue factor pathway inhibitor (TFPI). It functions to decrease the amount of TFPI, which is a natural anticoagulant. This type of “balancing therapy” works by creating a favorable ratio of procoagulants and anticoagulants, and may be seen more in the future as a treatment for a variety of bleeding and clotting disorders, as its effect is not dependent on the specific clotting factor deficit. 

What are inhibitors?

Patients can develop inhibitors (antibodies) to factor VIII and IX with recurrent replacement. This is more common in patients with specific mutations and/or severe hemophilia who don’t have any endogenous factor. 

The highest risk for development of inhibitors is in the first 20 exposures, and most people who are going to develop an inhibitor will do so by 50 exposures. Emicizumab has lessened this risk, because fewer patients are requiring factor. For those patients on factor replacement, frequent monitoring of inhibitor status is important. 

What about cost?

Hemophilia medications are extremely expensive. In the US, patient assistance programs through drug manufacturers help ensure access to hemophilia medications, especially for children. However, high medication costs create a global health equity issue; worldwide, many patients are unable to access prophylactic medications due to cost.

How do you adjust medications for planned procedures?

The management of children who require procedures depends on their severity, their prophylaxis regimen, and the indicated procedure.

Typically, it’s recommended to give their normal prophylaxis 30-60 minutes before the procedure so the patient has a factor level close to 100% during the procedure.

Patients on emicizumab may or may not get factor prior to a procedure depending on their severity and degree of surgical hemostasis. Dr. Weyand’s practice is to give factor before a procedure to patients on emicizumab.

How do we manage children with acute bleeds?

Many families will manage an acute bleed at home given their understanding of bleeding symptoms and management. Patients with hemophilia should have at least one dose of factor at home and take it with them when traveling.

Factor replacement is the first line for children with hemophilia presenting with an acute bleed. The downside, if any, is development of inhibitors but the risk/benefit nearly always favors factor replacement. Factor administration should not be delayed for imaging. 

Approximately 97% of bleeding episodes will resolve with one infusion of efanesoctocog alfa (von Drygalski et al. 2023). Therefore, some children who receive an infusion in the ED may not need to be admitted, though children who receive factor with a shorter half life may warrant admission for observation.

If a child comes in with unprovoked bleed (i.e. no known trauma), consider checking for an inhibitor, particularly if they’re adherent to good prophylaxis.

It’s important to remember that children with hemophilia can also have other injuries that should not be missed due to focusing on bleeding.

How do you manage keeping children safe while allowing them to be active kids?

Shared decision making is important, as with any other medical decision. 

What activities can they participate in?

Children with hemophilia generally shouldn’t play contact sports, including but not limited to football, wrestling, and boxing. The National Bleeding Disorder Foundation provides guidelines on relative risks of various activities.

What about head trauma?

It can be difficult to define specific guidelines about when parents should bring children in for head traumas, other than that they should have a lower threshold to seek care than for children without hemophilia. If there is any concern, they should call their doctor or come to the ED for evaluation.

What therapies are in development?

Gene therapies for hemophilia A and B were approved recently in adults with some studies ongoing in children. However, gene therapy isn’t necessarily for each patient and factor production wanes over time.

Fitusiran is a siRNA molecule designed to decrease antithrombin levels, therefore rebalancing procoagulants and anticoagulants. This type of balancing therapy may provide broad hemostasis, as they don’t depend on the particular clotting factor deficit. 

Resources

The World Federation of Hemophilia (WFH) is a non-profit organization dedicated to improving and sustaining care for people with inherited bleeding disorders around the world, including publishing international guidelines on diagnosis and management.

The Women and Girls with Bleeding Disorders (WGBD) initiative aims to improve diagnosis and treatment of bleeding disorders among patients identifying as female.

Goal

Listeners will explain the basic pathophysiology, diagnosis, and management of hemophilia A and B to improve both inpatient emergent care and outpatient counseling. 

Learning Objectives

After listening to this episode listeners will…  

1. Recall the basic inheritance and pathophysiology of hemophilia A and B.
2. Be familiar with the diagnostic workup of clotting disorders.
3. Describe the rationale and administration of clotting factor replacement.
4. Describe initial management of a child with hemophilia presenting with symptoms of acute bleeding.

Disclosures

Dr. Weyand has been a consultant for Takeda, Bayer, Genentech, and Sanofi. The content provided is for educational purposes only and does not endorse any specific products or companies. All references to medications or treatments use generic names to maintain objectivity and avoid commercial bias.

The Cribsiders report no relevant financial disclosures. 

Citation

Lidsky, H, Weyand, AC, Rago, AR, Masur, S. “#144: Fun Facts for Factor VIII (or XI): Managing Hemophilia”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ June 18, 2025.