Overview
Definition:
Hemophilia A and B are X-linked recessive genetic disorders characterized by a deficiency or dysfunction of coagulation factor VIII (Hemophilia A) or factor IX (Hemophilia B), leading to impaired blood clotting and a tendency for spontaneous and prolonged bleeding
These are the most common inherited severe bleeding disorders.
Epidemiology:
Hemophilia A affects approximately 1 in 5,000 to 10,000 live male births globally
Hemophilia B is less common, occurring in about 1 in 20,000 to 30,000 live male births
Prevalence is similar across ethnic groups and geographic regions
About 30% of cases arise from new mutations.
Clinical Significance:
Effective management of hemophilia is crucial to prevent debilitating joint damage, life-threatening hemorrhages, and improve long-term quality of life for affected children
Understanding factor replacement strategies and the role of DDAVP is essential for pediatricians and hematologists preparing for postgraduate examinations.
Clinical Presentation
Symptoms:
Severity of bleeding correlates with the level of factor deficiency
Mild: bleeding after trauma or surgery
Moderate: bleeding with minor trauma
Severe: spontaneous bleeding into joints (hemarthroses) and muscles (hematomas), often starting in infancy
Chief complaints may include: Prolonged bleeding after circumcision
Easy bruising
Bleeding from gums
Joint pain and swelling (hemarthrosis)
Muscle hematomas
Intracranial hemorrhage (rare but life-threatening)
Gastrointestinal or genitourinary bleeding.
Signs:
Physical examination findings may include: Petechiae and ecchymoses
Swollen, warm, painful joints
Deep muscle hematomas causing pain, swelling, and limited range of motion
Signs of anemia if chronic blood loss
Neurological deficits if CNS bleeding occurs
Vital signs may be normal unless significant hemorrhage leads to hypovolemia.
Diagnostic Criteria:
Diagnosis is based on clinical suspicion and laboratory confirmation
Key laboratory findings include: Prolonged activated partial thromboplastin time (aPTT)
Normal prothrombin time (PT)
Low levels of Factor VIII activity in Hemophilia A
Low levels of Factor IX activity in Hemophilia B
Specific factor assays to quantify the residual activity of the deficient factor
Genetic testing can confirm the diagnosis and identify specific mutations.
Diagnostic Approach
History Taking:
Detailed birth history (e.g., circumcision bleeding)
Family history of bleeding disorders in males or females (carriers)
History of previous unexplained bleeding episodes, prolonged bleeding after procedures or minor trauma
Presence of spontaneous joint or muscle bleeds
Red flags: Neonatal intracranial hemorrhage
Excessive bleeding in infants after minor falls.
Physical Examination:
Systematic examination focusing on signs of bleeding: Joints: Assess for swelling, tenderness, effusion, reduced range of motion
Muscles: Palpate for hematomas, check for tenderness and function
Skin: Look for bruises, petechiae
Neurological exam: Assess for signs of intracranial hemorrhage (lethargy, vomiting, focal deficits).
Investigations:
Screening tests: Complete blood count (CBC) with differential and peripheral smear
Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
Confirmatory tests: Factor VIII activity assay (for Hemophilia A)
Factor IX activity assay (for Hemophilia B)
Mixing studies (to differentiate factor deficiency from inhibitors)
Von Willebrand factor (VWF) antigen and activity (to rule out von Willebrand disease)
Bethesda assay for factor VIII inhibitors if response to therapy is poor.
Differential Diagnosis:
Other inherited bleeding disorders: Von Willebrand disease (most common)
Platelet function defects
Other factor deficiencies (e.g., Factor XI deficiency)
Acquired causes of bleeding: Liver disease
Vitamin K deficiency
Disseminated intravascular coagulation (DIC)
Anticoagulant overdose.
Management
Initial Management:
Immediate goal is to stop active bleeding and prevent complications
For hemarthrosis: RICE protocol (Rest, Ice, Compression, Elevation)
Pain management with analgesics (avoid NSAIDs due to antiplatelet effects)
Prompt administration of factor concentrate is crucial.
Medical Management:
Factor Replacement Therapy: The mainstay of treatment
Administered intravenously
Aim: To raise the plasma level of the deficient factor to a level that allows hemostasis
Dosages are calculated based on the patient's weight, the desired factor level, and the severity of bleeding
For Hemophilia A: Factor VIII concentrates (recombinant or plasma-derived)
For Hemophilia B: Factor IX concentrates (recombinant or plasma-derived)
Dosage formula: Units needed = Body weight (kg) x Desired factor increase (%) x 0.5 (for FVIII) or 1.0 (for FIX)
Target levels: Minor bleeding: 20-40%
Moderate bleeding/surgery: 40-60%
Severe bleeding/major surgery: 80-100%
Prophylaxis: Regular infusions to prevent bleeding, especially in severe hemophilia (typically 2-3 times/week)
DDAVP (1-desamino-8-D-arginine vasopressin): A synthetic analog of vasopressin
Effective for mild Hemophilia A and mild/moderate von Willebrand disease (Type I)
Stimulates release of stored Factor VIII and VWF from endothelial cells
Route: Intravenous or intranasal
Dosing: IV: 0.3 mcg/kg every 12-24 hours
Intranasal: 150-300 mcg every 12-24 hours (absorption is variable)
Contraindications: Severe Hemophilia A (FVIII < 30%), Hemophilia B, patients with significant cardiac or renal insufficiency, known hypersensitivity.
Surgical Management:
Indications: Rarely required for bleeding itself
May be indicated for complications like joint contractures requiring synovectomy or for placement of venous access devices
Pre-operative factor replacement is essential to achieve adequate hemostatic levels.
Supportive Care:
Physical therapy: Crucial for maintaining joint function and rehabilitation after bleeds
Education: Patient and family education on recognizing bleeding signs, administering factor concentrates, and managing hemophilia
Psychological support: Addressing the chronic nature of the disease and its impact on the child and family
Regular dental care: To prevent oral bleeding and infections.
Complications
Early Complications:
Acute joint hemorrhage leading to pain and immobility
Muscle hematomas causing compartment syndrome
Life-threatening bleeding: intracranial, gastrointestinal, airway obstruction.
Late Complications:
Chronic arthropathy: Joint destruction, pain, deformity, and loss of function due to recurrent hemarthroses
Pseudotumors: Large, expanding hematomas that can compress surrounding structures
Inhibitor formation: Development of antibodies against infused factor concentrates, rendering treatment ineffective.
Prevention Strategies:
Consistent adherence to factor replacement prophylaxis
Prompt treatment of all bleeding episodes
Physical therapy and joint protection measures
Patient and family education to avoid activities with high risk of trauma
Regular medical follow-up with a hemophilia treatment center.
Prognosis
Factors Affecting Prognosis:
Severity of hemophilia (factor level)
Age at diagnosis and initiation of treatment
Availability and adherence to factor replacement therapy (including prophylaxis)
Development of inhibitors
Quality of comprehensive care provided by hemophilia centers.
Outcomes:
With modern management, including prophylaxis and comprehensive care, individuals with hemophilia can lead relatively normal lives with significantly reduced bleeding and improved joint health
Life expectancy has dramatically increased
However, chronic joint disease and inhibitor development remain significant challenges.
Follow Up:
Regular follow-up with a pediatric hematologist and a comprehensive hemophilia treatment center is essential
This includes monitoring factor levels, assessing joint health, screening for inhibitors, and providing ongoing education and support
Annual comprehensive assessments are recommended.
Key Points
Exam Focus:
Differentiate Hemophilia A and B (Factor VIII vs
IX)
Understand the principles of factor replacement dosing (units, target levels)
Recognize indications for DDAVP and its limitations (mild Hemophilia A only)
Identify key diagnostic lab findings (prolonged aPTT, normal PT)
DNB/NEET SS exams often present case scenarios involving spontaneous bleeds, hemarthroses, and management of acute bleeds.
Clinical Pearls:
Always consider hemophilia in any infant or child with unexplained bleeding, especially joint or muscle hemorrhages
Early and adequate factor replacement is paramount
Avoid NSAIDs in patients with known or suspected hemophilia
Educate families on home infusion therapy for prophylaxis and on-demand treatment
In patients with inhibitor development, consider bypassing agents or factor VIII/IX concentrates with high specific activity.
Common Mistakes:
Delaying factor replacement therapy for acute bleeds
Using NSAIDs for pain management
Inadequate dosing of factor concentrates
Misinterpreting laboratory results (e.g., confusing prolonged PT with isolated prolonged aPTT)
Over-reliance on DDAVP for severe hemophilia or Hemophilia B.