Hemophilia B, also known as Christmas disease or the royal disease , is a congenital bleeding disorder caused by a deficiency or dysfunction of coagulation factor IX. It is inherited in an X-linked recessive pattern and leads to impaired blood clotting , resulting in a tendency for spontaneous or excessive bleeding after trauma or surgical procedures.
Hemophilia B is clinically indistinguishable from Hemophilia A (factor VIII deficiency), but is approximately four times less common , affecting about 1 in 75,000 male births worldwide. It affects all ethnic groups equally.
Why Is It Called “Christmas Disease”?
The disorder is eponymously named after Stephen Christmas , the first patient described with the condition in 1952. Notably, Hemophilia B was prevalent among European royal families , especially descendants of Queen Victoria , leading to its alternate name: the royal disease .
Etiology and Genetics
Hemophilia B results from mutations in the F9 gene , located on the X chromosome (Xq27.1-q27.2) . The F9 gene encodes coagulation factor IX , a vitamin K–dependent serine protease essential for blood clotting.
Inheritance Pattern
- X-linked recessive .
- Affected males inherit the mutated X chromosome from carrier mothers .
- Females with one mutated X are typically asymptomatic carriers , but may present with mild symptoms depending on X-chromosome inactivation (lyonization) .
- "True" hemophiliac females are rare and occur only if:
- The female inherits two mutated X chromosomes.
- There is extreme skewing of X-inactivation.
- One X is mutated, and the other is lost (Turner syndrome, XO).
De Novo Mutations
- ~30–33% of Hemophilia B cases result from spontaneous mutations , with no prior family history .
Pathophysiology
Factor IX is a crucial component of the intrinsic coagulation cascade . Upon activation by factor XIa, it forms a complex with factor VIIIa , calcium ions, and phospholipids on platelet surfaces, leading to the activation of factor X . Activated factor X (Xa) then converts prothrombin to thrombin , which facilitates fibrin clot formation .
Deficiency Consequences
- Impaired generation of thrombin.
- Inadequate fibrin clot formation.
- Increased risk of spontaneous bleeding or prolonged bleeding after injury/surgery.
Clinical Features
Severity Classification
| Severity | Factor IX Activity | Clinical Presentation |
|---|---|---|
| Mild | 6–49% | Bleeding with trauma/surgery |
| Moderate | 1–5% | Rare spontaneous bleeding, bleeding with minor trauma |
| Severe | <1% | Frequent spontaneous bleeding, especially into joints and muscles |
Common Bleeding Sites
- Hemarthrosis (joints – knees, elbows, ankles)
- Muscle hematomas
- Epistaxis (nosebleeds)
- Hematuria
- Gastrointestinal bleeding (melena, hematochezia)
- Intracranial hemorrhage (life-threatening)
- Prolonged bleeding post-circumcision or tooth extraction
Hemophilia B Leyden
- A rare variant characterized by severe bleeding in childhood with spontaneous improvement after puberty due to androgen-responsive elements in the F9 promoter region .
Diagnosis
Clinical Evaluation
- Detailed personal and family history of bleeding.
- History of excessive bleeding after minor trauma or surgery .
- Joint pain/swelling from recurrent hemarthroses.
Laboratory Investigations
| Test | Expected Result |
|---|---|
| Prothrombin Time (PT) | Normal |
| Thrombin Time (TT) | Normal |
| Bleeding Time | Normal |
| Activated Partial Thromboplastin Time (aPTT) | Prolonged |
| Factor IX assay | Decreased |
| Factor VIII, vWF assays | Normal |
| Genetic testing (F9 mutation analysis) | Confirms diagnosis and risk of inhibitor development |
Complications
- Chronic arthropathy due to repeated hemarthroses.
- Inhibitor development : Some patients develop neutralizing antibodies (inhibitors) against factor IX.
- Psychosocial burden due to chronic disease and disability.
- Complications from treatment : Viral infections (historically), allergic reactions, thrombosis.
Management and Treatment
General Principles
- Patient education : Genetic counseling, early bleeding recognition, avoid trauma.
- Avoid NSAIDs , especially aspirin , due to platelet inhibition.
- Multidisciplinary care : Hematologists, orthopedic surgeons, physiotherapists.
Factor Replacement Therapy
1. Recombinant Factor IX
- First-line therapy.
- On-demand or prophylactic infusion.
- Long-acting formulations available.
2. Plasma-derived Factor IX Concentrates
- Alternative when recombinant products are unavailable.
3. Fresh Frozen Plasma (FFP)
- Only used in emergencies or when factor IX is unavailable.
Other Therapies
- Tranexamic acid : Antifibrinolytic agent used adjunctively, especially for mucosal bleeding.
- Gene therapy (emerging): Promising treatment with AAV vector–based F9 gene transfer , currently under trial or limited clinical use.
Inheritance Counseling
- All daughters of affected males are obligate carriers .
- Female carriers have a 50% chance of transmitting the mutation to male offspring.
- Prenatal genetic testing or preimplantation genetic diagnosis (PGD) may be considered in high-risk families.
High-Yield Points
- Hemophilia B is caused by factor IX deficiency due to F9 gene mutations .
- It is X-linked recessive , affects males predominantly , and presents with prolonged bleeding .
- Prolonged aPTT with normal PT, TT, and bleeding time is typical.
- Treatment involves recombinant factor IX replacement.
- Prophylactic therapy improves quality of life and prevents complications.
- Genetic counseling is essential for affected families.
