Hemophilia C in Children

Hemophilia C Introduction Pathophysiology Clinical Presentation Diagnosis Management Complications Prognosis

Introduction to Hemophilia C in Children

Hemophilia C, also known as Factor XI deficiency or Rosenthal syndrome, is a rare bleeding disorder characterized by a deficiency in coagulation factor XI. Unlike hemophilia A and B, hemophilia C is inherited in an autosomal recessive manner, affecting both males and females equally. The prevalence of hemophilia C varies among populations, being more common in Ashkenazi Jews (occurring in about 8% of the population) but rare in other ethnic groups.

In children, the diagnosis and management of hemophilia C can be challenging due to its variable clinical presentation and the lack of correlation between factor XI levels and bleeding tendency. The severity of hemophilia C is generally classified based on factor XI activity levels:

• Severe: <15% of normal FXI activity
• Moderate: 15-20% of normal FXI activity
• Mild: 20-70% of normal FXI activity

However, it's important to note that these classifications do not reliably predict bleeding risk, as some individuals with very low FXI levels may not experience significant bleeding, while others with higher levels may have bleeding tendencies.

Understanding the unique aspects of hemophilia C, including its pathophysiology, clinical presentation, diagnostic challenges, and management strategies, is crucial for healthcare professionals treating affected children.

Pathophysiology of Hemophilia C

Hemophilia C results from mutations in the F11 gene, located on chromosome 4. This gene encodes for coagulation factor XI, a component of the intrinsic pathway of blood coagulation. The pathophysiology involves:

1. Genetic basis:
   • Over 220 different mutations have been identified in the F11 gene, including missense, nonsense, splice site mutations, and deletions.
   • Autosomal recessive inheritance pattern, requiring both parents to be carriers for a child to be affected.
2. Factor XI deficiency:
   • Reduced or absent functional factor XI leads to impaired activation of factor IX in the intrinsic pathway.
   • This results in decreased thrombin generation, particularly in areas of high fibrinolytic activity.
3. Altered coagulation cascade:
   • Factor XI deficiency primarily affects the intrinsic pathway of coagulation.
   • The extrinsic and common pathways remain largely unaffected, which may explain the milder bleeding tendency compared to hemophilia A and B.
4. Impaired thrombin generation:
   • Factor XI plays a role in the sustained generation of thrombin, which is important for clot stability.
   • Deficiency leads to decreased thrombin-activatable fibrinolysis inhibitor (TAFI) activation, potentially increasing susceptibility to fibrinolysis.
5. Tissue-specific effects:
   • Bleeding tendency is more pronounced in tissues with high fibrinolytic activity, such as the oral cavity, nasal mucosa, and urinary tract.

Unique aspects of factor XI in hemostasis:

• Factor XI is activated by thrombin in a feedback loop, contributing to sustained thrombin generation.
• It plays a more significant role in maintaining clot stability rather than initial clot formation.
• The bleeding tendency in hemophilia C is less predictable compared to other factor deficiencies, suggesting complex interactions with other hemostatic mechanisms.

Understanding these pathophysiological mechanisms is crucial for interpreting the variable clinical presentation and developing appropriate management strategies for children with hemophilia C.

Clinical Presentation of Hemophilia C in Children

The clinical presentation of hemophilia C in children is highly variable and often milder compared to hemophilia A and B. Many affected individuals may remain asymptomatic until they experience trauma or undergo surgery. Key features of the clinical presentation include:

1. Bleeding tendency:
   • Generally milder than in hemophilia A or B
   • Often trauma-related rather than spontaneous
   • More common in areas with high fibrinolytic activity
2. Common bleeding manifestations:
   • Epistaxis (nosebleeds)
   • Oral cavity bleeding, especially after dental procedures
   • Menorrhagia in adolescent females
   • Prolonged bleeding after surgery or trauma
   • Easy bruising
3. Less common presentations:
   • Hemarthrosis (joint bleeds) - rare compared to hemophilia A and B
   • Muscle hematomas
   • Gastrointestinal bleeding
   • Hematuria
4. Age-related considerations:
   • Newborns: Usually asymptomatic, may have prolonged umbilical stump bleeding
   • Infants and toddlers: May present with prolonged bleeding after circumcision or other minor procedures
   • School-age children: Increased risk of trauma-related bleeding
   • Adolescents: Menorrhagia in females, increased risk with sports participation

Important clinical characteristics of hemophilia C:

• Lack of correlation between factor XI levels and bleeding tendency
• Significant variability in bleeding phenotype, even within families with the same mutation
• Absence of spontaneous joint or muscle bleeds in most cases
• Potential for severe bleeding with surgery, particularly in areas of high fibrinolytic activity

The variable and often mild nature of hemophilia C can lead to delayed diagnosis in children. Healthcare providers should maintain a high index of suspicion, especially in children with a family history of bleeding disorders or those from populations with higher prevalence of factor XI deficiency.

Diagnosis of Hemophilia C in Children

Diagnosing hemophilia C in children can be challenging due to its variable clinical presentation and the lack of correlation between factor XI levels and bleeding tendency. The diagnostic approach includes:

1. Clinical evaluation:
   • Detailed personal and family history of bleeding disorders
   • Physical examination focusing on evidence of bleeding
   • Assessment of bleeding patterns and severity
2. Laboratory tests:
   • Complete blood count (CBC)
   • Prothrombin time (PT) - usually normal
   • Activated partial thromboplastin time (aPTT) - may be normal or prolonged
   • Factor XI activity assay - crucial for diagnosis
   • Factor VIII and IX assays to exclude other hemophilias
3. Genetic testing:
   • F11 gene mutation analysis for confirmation and family counseling
   • Useful for prenatal diagnosis and carrier detection
4. Additional coagulation studies:
   • Thrombin generation assays
   • Rotational thromboelastometry (ROTEM) or thromboelastography (TEG)
   • These tests may provide additional information on overall clotting function

Diagnostic challenges specific to hemophilia C:

• Normal aPTT does not exclude the diagnosis, as some patients with factor XI deficiency may have normal aPTT
• Factor XI levels do not reliably predict bleeding risk
• Mild cases may be missed on routine preoperative coagulation screening
• Distinguishing from other rare bleeding disorders with similar presentations

Diagnostic considerations in children:

• Age-appropriate normal ranges for factor XI levels should be used
• Repeat testing may be necessary as factor XI levels can fluctuate
• Family testing is often helpful, given the autosomal recessive inheritance pattern
• Consider testing in children from high-risk populations (e.g., Ashkenazi Jews) even with mild bleeding symptoms

Early and accurate diagnosis is essential for appropriate management and prevention of bleeding complications, particularly before surgical procedures. Diagnosis should be made at specialized coagulation laboratories with experience in factor assays and genetic testing for rare bleeding disorders.

Management of Hemophilia C in Children

The management of hemophilia C in children focuses on preventing and treating bleeding episodes, with strategies tailored to the individual patient's bleeding phenotype rather than factor XI levels alone. Key components of management include:

1. Factor replacement therapy:
   • Fresh Frozen Plasma (FFP) or Factor XI concentrate (where available)
   • Used primarily for perioperative management or treatment of severe bleeding
   • Dosing is challenging due to variable relationship between factor levels and bleeding risk
2. Antifibrinolytic agents:
   • Tranexamic acid or epsilon-aminocaproic acid
   • Particularly useful for mucosal bleeding (e.g., epistaxis, menorrhagia)
   • Can be used alone or in combination with factor replacement
3. Topical hemostatic agents:
   • Fibrin glue or thrombin-based products
   • Useful for localized bleeding, especially during dental procedures
4. Hormonal therapy:
   • Combined oral contraceptives or levonorgestrel-releasing intrauterine devices
   • For management of menorrhagia in adolescent females
5. Desmopressin (DDAVP):
   • May be effective in some patients, but response is variable
   • Trial recommended before using in clinical situations
6. Preventive measures:
   • Avoidance of antiplatelet agents and anticoagulants when possible
   • Caution with contact sports and activities with high risk of trauma
   • Regular dental care to prevent gingival bleeding
7. Perioperative management:
   • Individualized planning based on the patient's bleeding history and the type of surgery
   • May involve factor replacement, antifibrinolytics, and close monitoring
8. Education and counseling:
   • Patient and family education on recognizing and managing bleeding episodes
   • Genetic counseling for family planning

Special considerations for hemophilia C management in children:

• Prophylaxis is not typically required, unlike in severe hemophilia A or B
• Management is often event-driven rather than routine
• Importance of creating individualized treatment plans based on bleeding history
• Coordination with pediatric hematologists for complex cases or surgical procedures

Emerging therapies:

• Factor XI-targeted therapies (e.g., antisense oligonucleotides, monoclonal antibodies) are in development and may offer new treatment options in the future

Management strategies should be tailored to the individual child's needs, considering their bleeding history, activity level, and family preferences. Regular follow-up with a pediatric hematologist is important for optimizing management and addressing any concerns or complications.

Complications of Hemophilia C in Children

While hemophilia C is generally milder than hemophilia A or B, children with this condition can still experience complications, particularly related to bleeding episodes or treatment. Key complications include:

1. Bleeding-related complications:
   • Anemia due to recurrent or severe bleeding episodes
   • Prolonged wound healing after injuries or surgical procedures
   • Rarely, intracranial hemorrhage following head trauma
2. Oral and dental complications:
   • Gingival bleeding and increased risk of dental caries due to poor oral hygiene
   • Complications from dental extractions or procedures if not properly managed
3. Gynecological issues:
   • Iron-deficiency anemia in adolescent females due to menorrhagia
   • Potential complications during childbirth later in life
4. Perioperative complications:
   • Excessive bleeding during or after surgical procedures
   • Delayed wound healing and increased risk of infection
5. Treatment-related complications:
   • Allergic reactions to blood products or factor concentrates
   • Transfusion-related complications when using Fresh Frozen Plasma (FFP)
   • Rare risk of transmission of blood-borne pathogens with plasma-derived products
   • Potential for thrombotic events with excessive factor XI replacement
6. Psychosocial complications:
   • Anxiety related to unpredictable bleeding episodes
   • Limitations in physical activities or sports participation
   • Impact on school attendance and academic performance
   • Family stress related to managing a chronic condition
7. Delayed diagnosis complications:
   • Unexpected bleeding during minor procedures if the condition is undiagnosed
   • Potential for more severe bleeding episodes before appropriate management is initiated
8. Rare complications:
   • Development of inhibitors to factor XI (extremely rare)
   • Compartment syndrome from severe muscle bleeds (uncommon in hemophilia C)

Important considerations regarding complications in hemophilia C:

• Complications are generally less severe and less frequent compared to hemophilia A and B
• Joint bleeds (hemarthrosis) and resulting arthropathy are rare in hemophilia C
• The unpredictable nature of bleeding in hemophilia C can lead to unexpected complications
• Long-term joint and muscle complications are less common than in other types of hemophilia

Prevention and management of complications:

• Regular follow-up with a pediatric hematologist
• Individualized bleeding prevention strategies based on the child's specific bleeding phenotype
• Proper dental hygiene and regular dental check-ups
• Age-appropriate education for the child and family about recognizing and managing bleeding episodes
• Psychological support and counseling when needed
• Careful planning for surgical procedures and invasive interventions

While complications in hemophilia C are generally less severe than in other forms of hemophilia, early recognition and appropriate management are crucial to minimize their impact on the child's health and quality of life. A multidisciplinary approach involving hematologists, pediatricians, dentists, and mental health professionals can help address the various aspects of care for children with hemophilia C.

Prognosis of Hemophilia C in Children

The prognosis for children with hemophilia C is generally favorable, with most individuals experiencing a milder clinical course compared to those with hemophilia A or B. Key factors affecting prognosis include:

1. Individual bleeding phenotype:
   • Highly variable, even among individuals with similar factor XI levels
   • Some children may have minimal bleeding tendencies, while others experience more frequent episodes
2. Early diagnosis and appropriate management:
   • Timely diagnosis allows for proper precautions and treatment during high-risk situations
   • Appropriate perioperative management significantly reduces surgical complications
3. Access to specialized care:
   • Regular follow-up with pediatric hematologists improves outcomes
   • Availability of factor XI concentrates or appropriate blood products when needed
4. Patient and family education:
   • Understanding of the condition leads to better self-management and prompt treatment of bleeding episodes
5. Adherence to preventive measures:
   • Proper dental hygiene and regular check-ups can prevent oral complications
   • Appropriate activity modifications can reduce trauma-related bleeding

Long-term outlook for children with hemophilia C:

• Normal life expectancy in most cases
• Minimal to no long-term joint damage, unlike in severe hemophilia A or B
• Potential for normal participation in most activities with proper precautions
• Successful management of menorrhagia in adolescent females with appropriate interventions
• Generally good quality of life with proper management and support

Considerations for different life stages:

• Infancy and early childhood: Main concerns relate to accidental injuries and proper management of minor procedures
• School-age: Focus on education about the condition and safe participation in physical activities
• Adolescence: Management of menorrhagia in females, career and lifestyle counseling
• Adulthood: Considerations for more complex surgical procedures, family planning

Areas of ongoing research that may impact future prognosis:

• Development of novel factor XI-targeted therapies
• Improved understanding of the role of factor XI in coagulation, potentially leading to better predictive models for bleeding risk
• Advances in personalized medicine approaches for tailoring treatment to individual patients

While hemophilia C presents challenges, particularly in terms of its unpredictable bleeding phenotype, the overall prognosis for affected children is good. With appropriate management, most individuals with hemophilia C can lead normal, active lives. Regular medical follow-up, patient and family education, and a proactive approach to managing bleeding risks are key to achieving the best possible outcomes for children with this condition.

Hemophilia C in Children

1. What is Hemophilia C?
   Hemophilia C is a rare inherited bleeding disorder caused by a deficiency in Factor XI.
2. What is another name for Hemophilia C?
   Hemophilia C is also known as Factor XI deficiency or Rosenthal syndrome.
3. How is Hemophilia C inherited?
   Hemophilia C is inherited in an autosomal recessive pattern, meaning both parents must pass on the defective gene for a child to be affected.
4. Which chromosome contains the gene responsible for Hemophilia C?
   The gene responsible for Hemophilia C (F11) is located on chromosome 4.
5. How common is Hemophilia C compared to Hemophilia A and B?
   Hemophilia C is much rarer than Hemophilia A and B, affecting approximately 1 in 100,000 individuals in the general population.
6. Which ethnic group has a higher prevalence of Hemophilia C?
   Hemophilia C is more prevalent in Ashkenazi Jews, affecting about 8% of this population.
7. What are the typical symptoms of Hemophilia C in children?
   Symptoms may include easy bruising, prolonged bleeding after injury or surgery, and nosebleeds. However, symptoms are often milder than in Hemophilia A or B.
8. How is Hemophilia C diagnosed in children?
   Diagnosis is made through blood tests that measure Factor XI levels and activity, often prompted by a family history or unexplained bleeding episodes.
9. At what age are children typically diagnosed with Hemophilia C?
   Unlike Hemophilia A and B, Hemophilia C may not be diagnosed until later childhood or even adulthood due to its milder nature.
10. Can girls be affected by Hemophilia C?
    Yes, unlike Hemophilia A and B which primarily affect males, Hemophilia C affects both males and females equally due to its autosomal inheritance pattern.
11. What is the normal range for Factor XI levels in the blood?
    The normal range for Factor XI levels is typically between 70-150% of average.
12. How are Factor XI levels classified in Hemophilia C?
    Factor XI levels are classified as severe (<15%), moderate (15-30%), or mild (30-50%).
13. What complications can arise from untreated Hemophilia C in children?
    Potential complications include joint damage from recurrent bleeds, anemia from blood loss, and excessive bleeding during surgical procedures.
14. How is Hemophilia C treated in children?
    Treatment typically involves replacement of Factor XI through fresh frozen plasma or Factor XI concentrates, often given before surgery or after injury.
15. Is gene therapy a potential treatment for Hemophilia C?
    While gene therapy is being explored for Hemophilia A and B, it is not currently a viable treatment option for Hemophilia C.
16. What precautions should children with Hemophilia C take in daily life?
    Children should avoid contact sports, wear protective gear during physical activities, and inform healthcare providers about their condition before any medical procedures.
17. Can children with Hemophilia C participate in physical education classes?
    Yes, with proper precautions and modifications. Activities should be discussed with the child's hematologist to ensure safety.
18. How does Hemophilia C affect a child's growth and development?
    Generally, Hemophilia C does not significantly impact a child's growth and development, especially when properly managed.
19. What is the life expectancy for children diagnosed with Hemophilia C?
    With proper management, individuals with Hemophilia C typically have a normal life expectancy.
20. Are there any dietary restrictions for children with Hemophilia C?
    There are no specific dietary restrictions, but a balanced diet rich in iron can help prevent anemia.
21. How often should children with Hemophilia C have check-ups with a hematologist?
    Regular check-ups are recommended, typically every 6-12 months, or more frequently if there are complications or concerns.
22. Can Hemophilia C be cured?
    Currently, there is no cure for Hemophilia C, but it can be effectively managed with proper treatment.
23. What is the role of genetic counseling in families affected by Hemophilia C?
    Genetic counseling can help families understand the inheritance pattern, assess risks for future pregnancies, and make informed decisions about family planning.
24. How does stress affect children with Hemophilia C?
    Stress can potentially exacerbate bleeding tendencies, so stress management techniques may be beneficial for children with Hemophilia C.
25. Are vaccinations safe for children with Hemophilia C?
    Yes, vaccinations are generally safe, but should be given subcutaneously rather than intramuscularly to reduce the risk of muscle bleeds.
26. What emergency measures should be taken if a child with Hemophilia C experiences a severe bleed?
    Immediate medical attention should be sought, and the child's hematologist should be contacted. Factor XI replacement therapy may be necessary.
27. How does Hemophilia C affect dental care in children?
    Children with Hemophilia C may require factor replacement before dental procedures. Good oral hygiene is crucial to prevent gum bleeding.
28. Can children with Hemophilia C receive routine immunizations?
    Yes, but they should be given subcutaneously rather than intramuscularly, and under the guidance of a hematologist.
29. What psychological support might be beneficial for children with Hemophilia C?
    Counseling, support groups, and education about the condition can help children cope with the challenges of living with Hemophilia C.
30. How does Hemophilia C differ from von Willebrand disease?
    While both are bleeding disorders, Hemophilia C is caused by Factor XI deficiency, whereas von Willebrand disease is caused by a deficiency or dysfunction of von Willebrand factor.

Further Reading

• How I treat factor XI deficiency (Blood Journal)
• Factor XI deficiency: from molecular genetics to clinical management (Journal of Thrombosis and Haemostasis)
• GeneReviews: Factor XI Deficiency
• National Hemophilia Foundation: Factor XI Deficiency
• WFH Guidelines for the Management of Hemophilia, 3rd edition (includes section on rare bleeding disorders)