Pediatric Hemophilia — Pathophysiology and Types

Image: “Bleeding finger” by Crystal (Crystl) from Bloomington, USA. License: CC BY 2.0

Discussion of Pediatric Hemophilia

Hemophilia is a rare blood clotting disorder in which the body lacks blood-clotting factors. Hemophiliac patients will continue bleeding for more prolonged durations after injury. Bleeding can occur spontaneously or after minor trauma. The disease can also lead to internal bleeding, which might be life-threatening.

The joints, such as the elbows, knees, and ankles, manifest the signs and symptoms of bleeding. Bleeding from the GI tract, brain, and internal organs could go unnoticed, causing the patient to go into hypovolemic shock.

Hemophilia has two basic types – Hemophilia A and Hemophilia B. Hemophilia C is very rare, and patients sustain far less bleeding than type A or B. Hemophilia A and B mostly occur in male children because the disease is X-linked recessive.

Image: “2928 X-linked Recessive Inheritance-new” by OpenStax College. License: CC BY 3.0

There are three ways to get this disorder:

• Inherited (X-linked recessive)
• Spontaneous mutations
• Acquired immunological defects

Hemophilia A

This X-linked disorder is caused by the deficiency of clotting factor VIII. It is the most common type of Hemophilia, occurring with a frequency of 1/4000.

Hemophilia B

Also known as Christmas disease, Hemophilia B occurs due to the deficiency of clotting factor IX. It constitutes 20% of the total Hemophilia cases. It is less common than Hemophilia A, occurring with a frequency of 1/20,000.

Hemophilia C

This type is rare and occurs due to the deficiency of factor XI. The symptoms are mild in intensity. It is not transmitted in an X-link recessive pattern, so both sexes are equally susceptible to the disease.

Etiology of Pediatric Hemophilia

The mutations occur in the genes that code for the proteins that make clotting factors. Blood clotting is a complex process that involves 13 clotting factors. The factors are written in Roman numerals between I and XIII.

When a blood vessel injury occurs, platelets get recruited to form a plug. Activated platelets release several chemicals to initiate the clotting cascade—finally, a mesh, which is made up of fibrin, forms. A final clot stops the bleeding and covers the injured areas. In hemophilia, the clotting factors are missing, so the process is defective, and bleeding does not stop.

Epidemiology

Congenital hemophilia A occurs in approximately 1 out of every 5000 men/boys. The frequency of congenital hemophilia B is around 1 for every 30,000 men/boys. About 400 children are born with hemophilia each year in the US.

Grading of Pediatric Hemophilia

• Mild: The concentration of the clotting factor (VIII or IX) is 5–40%
• Moderate: 1–5% of the clotting factors are available for the clotting mechanism
• Severe: < 1% of the clotting factors are present for the cascade

Symptoms and Signs of Pediatric Hemophilia

Symptoms and signs depend on disease severity. In severe form, the symptoms begin to appear early and with no apparent history of trauma or injury. The bleeding episodes start in the first or second year of life. The disease mostly gets diagnosed at the time of circumcision, when the bleeding cannot be controlled with traditional measures. In moderate and mild forms, the bleeding is more occasional with trauma or minor injuries. The general signs and symptoms of the disease are:

Image: “Medical X-Ray Imaging” by Nevit Dilmen. License: CC BY-SA 3.0

Haemarthrosis: ‘Haem’ is blood, and ‘arthrosis’ stands for joints, ‘bleeding in the joint spaces.’ It is a specific sign of the disease. Ankles and knees are more commonly affected than the smaller joints. Repeated bleeding can lead to joint destruction.

Bleeding into muscles: Hematoma formations can even lead to compartment syndrome.

Gastrointestinal tract bleeding: A small peptic ulcer will not heal, leading to continuous bleeding.

Urinary tract bleeding: It can present as haematuria.

Intracranial bleeds: Symptoms such as a headache, lethargy, nausea, and vomiting start to appear. It requires immediate treatment.

Bleeding after trauma and surgery: It is a common scenario in hemophilic children.

Diagnosis of Pediatric Hemophilia

There are three main steps of diagnosis. It is important to go step-wise because the warning signs can be missed.

Examination

After taking a thorough history of the patient, begin the general physical and systemic examination. All the systems should be examined in detail.

• Neurological: Look for any abnormal findings, altered mental status, and signs of meningism
• Musculoskeletal: Joint tenderness, warmth, swelling, and limited range of motion
• Gastrointestinal: Examine for hepatic or splenic tenderness and signs of peritonitis
• Genitourinary: Bladder distensions, irritation, and tenderness of costovertebral angles
• Other signs of airway obstruction and compartment syndrome should also be checked

Laboratory Investigations

• Complete blood cells count and hemoglobin levels
• Bleeding Time (BT) and clotting time (CT)
• Coagulation studies: PT (Prothrombin Time) and APTT (Activated Partial Thromboplastin Time)
• Factor VIII, IX, and vWF (Von Willebrand factor) Assays
• Testing for infections such as hepatitis or AIDS
• Genetic Testing

Differentiation between Hemophilia A and B on lab tests

Hemophilia A = Factor VIII is reduced. APTT and CT are prolonged. Platelet count, PT, and BT are normal.

Hemophilia B = Factor IX deficiency. APTT is prolonged. Platelet count and PT are normal.

Radiological Investigations

Image: “Knee ultrasound” by Nevit Dilmen. License: CC BY-SA 3.0

• Head CT to look for a hemorrhage
• Brain MRI
• Ultrasound for signs of effusions in the joint spaces

Management of Pediatric Hemophilia

General Approach

• Advise avoiding the trauma
• Do not use aspirin
• Immunization against infectious diseases like hepatitis
• Genetic counseling

Specific treatment

• Factor IX concentrates (Hemophilia B)
• Factor VIII concentrates (Hemophilia A)
• If the concentrates are not available, then consider these options:
  • Whole blood
  • Fresh frozen plasma
  • Cryoprecipitate
• Synthetic vasopressin analog, Desmopressin Acetate
• Antifibrinolytics: Aminocaproic Acid and Tranexamic acid
• Monoclonal antibodies (Rituximab)
• Analgesics (acetaminophen)

Overview:

Prognosis

With replacement therapy, patients with Hemophilia A now have considerably longer life expectancies. There is a 2 to 8% lifetime risk of intracranial bleeding with the condition. Out of all the patients with severe hemophilia, around 10% have intracranial bleeding. Compared to the healthy male population, the mortality rate is about two times higher for people with the condition and about four to six times higher for people with severe cases of the condition.