Bleeding Disorders in Childhood

• Haemophilia A and B are inherited bleeding disorders caused by deficiencies of clotting factor VIII (FVIII) and factor IX (FIX), respectively. They account for 90-95% of severe congenital coagulation factor deficiencies.
• The modern history of haemophilia dates back to 1803 with the description of haemophilic kindred by John Otto.
• FVIII isolated in 1937 by Patek and Taylor, which they called antihemophilia factor (AHF).
• Christmas disease was later recognized in 1952 (named after the 1ST patient to be studied in detail).
• 1964 marked the beginning of the “concentrate era’’, with the discovery of the usefulness of cryoprecipitate (factor VIII-rich blood fraction) in its treatment.
• Genes for both factors were cloned in 1985, with subsequent commercial production of the recombinant variants of the factors.

An X- linked recessive disorder. Gene for factor VIII & IX located on long arm of X-chromosome in bands q27 & q28. Genetic abnormalities resulting in this defect include; deletions of variable size, abnormalities with stop codons, and frame-shift defects. Recent data suggest that 45% the cases of severe hemophilia A result from an inversion mutation. Up to 5-10% & 40-50% of haemophilias A & B respectively, actually have a qualitative rather than quantitative defects of the relevant factors.

• Prevalence: 1:5,000. 85% haemophilia A, 15% B.
• Sex: Generally occur almost exclusively in males; however also could occur in females due to lyonization or presence of 2 independent mutations.
• Race: no racial preference.
• Age: can manifest at birth or later in life. Onset of manifestations depend on degree of deficiency.

• Presents with bleeding from various sites which could be provoked or spontaneous.
• Neonates: cord bleeding, post circumcision bleed, intracranial bleeding, sub-galeal haemorrhage etc.
• Infants: gum bleeding especially with teeth eruption common in this age group & could be difficult to control.
• Hemarthrosis which is the commonest manifestation of this condition, is usually seen in the toddlers and older age group as physical activity increases.
• They could also present with intramuscular hematomas especially involving the iliopsoas muscle.
• Gastrointestinal bleeding are rather unusual compared to VWD.
• Petechiae usually do not occur in patients with hemophilia as they are manifestations of capillary blood leaking, which typically is the result of vasculitis or abnormalities in the number or function of platelets.

Specific

• Clotting profile
• APTT usually prolonged; normal APTT however does not rule it out.
• PT, BT, Platelet count all normal.
• Factor VIII, IX assay.
• Pre-natal & carrier diagnosis is possible using either molecular techniques (Preferred) or via quantitative assay of the factors in utero (especially for FVIII).

Ancillary

• CBC
• ESR
• Lentiviral screening, HBsAg
• Joint Roentgenography

• Current treatment of patients with hemophilia requires a comprehensive multidisciplinary approach.
• A comprehensive team includes the Hematologist, Surgeons especially orthopedic, Dentist; nurses; Physiotherapists; social workers.
• Bedrock of management is replacement therapy with relevant factor concentrate.
• Management can be divided into 3 broad categories:
• Primary prophylaxis (gold standard): indicated for patients with moderate to severe condition. Aimed at maintaining factor level above 5%.
• Dose - 20 U/kg/day for Haemophilia A & 30 U/kg/day for B, on alternate days.
• Secondary prophylaxis: after target organ damage had started.
• Therapeutic use of concentrates: Less cost effective than prophylaxis

Dose of recombinant factor

• Dose of FVIII (Units) = (Required – Observed Level) X Weight (Kg) X 0.5
• Dose of FIX (Units) = (Required – Observed Level) X Weight (Kg) X 1.4

Other Modalities

• Desmopressin acetate: Promote release of formed FVIII.
• EACA: anti-fibrinolytic agent, useful for mucosal bleed.
• Patient Education: Avoidance of contact sports, IM injections (SC when feasible). Replacement therapy may be necessary prior to circumcision.
• Genetic counselling
• Definitive treatment – Gene therapy.

Haemorragic

• Chronic arthropathy
• Hematomas including intracranial
• Anaemia

Non-hemorrhagic

• Transfusion-related infections
• Development of factor inhibitors (antibodies).
• Low self esteem
• Psycho-social, financial strain.

• mucocutaneous haemorrage is characteristic.
• Bruising, epistaxis, menorrhagia and post-operative. Patients with type 3 may rarely have hemarthroses.
• Bleeding may however not occur during stressful events such as partutition as vWD is an acute phase reactant.

• Bleeding time
• PTTK
• vWF activity
• vWF antigen assay
• Factor VIII activity
• CBC & PBF

• DDAVP – induces release of vWF. Not useful in type 3.
• Fresh-frozen plasma/ cryoprecipitate. Contains both vWF and factor VIII.
• Antifibrinolytic agent e.g. e-aminocaproic acid.

• Widespread endothelial injury
• Profuse generation of tissue factor
• Suppresion of anticoagulant protein activity
• Intense inflammation

• Bleeding: initially from puncture sites, orifices, internal bleeds
• Purpura, petechiae, ecchymoses, haematoma
• Multiple organ failure

• Complete blood count
• Peripheral blood film examination – burr, helmet cells, schizocytes.
• Clotting profile – all deranged.
• FDP test, D-dimer assay for fibrinogen degradation products.
• Screen for trigger agent e.g. blood culture, urinalysis, m/c/s, malaria etc.

2 main principle of management

• Treat the trigger that caused DIC
• Restore normal homeostasis by correcting the shock, acidosis, and hypoxia that usually complicate DIC.

• In a child who appears well, immunemediated mechanisms are the most common cause of thrombocytopenia.
• Thrombocytopenia results from increased rates of antibody-dependent platelet destruction.
• Neonatal alloimmune thrombocytopenic purpura (NATP) occurs as a result of sensitization of the mother to antigens present on fetal platelets during gestation. Antibodies cross the placenta and attack the fetal platelet.
• Many platelet alloantigens have been identified and sequenced, permitting prenatal diagnosis of the condition in an at-risk fetus.
• Mothers with idiopathic thrombocytopenic purpura (maternal ITP) or with a history of ITP may have passive transfer of antiplatelet antibodies that react with fetal platelets, with resultant neonatal thrombocytopenia
• The maternal platelet count is sometimes a useful indicator of the probability that the infant will be affected.

Clinical Manifestations

• The infant with NATP is at risk for intracranial hemorrhage in utero and during the immediate delivery process.
• In ITP, the greatest risk seems to be present during passage through the birth canal, during which molding of the head may induce intracranial hemorrhage

Treatment

• Administration of IV immunoglobulin before delivery has been shown to be effective in increasing fetal platelet counts and may alleviate thrombocytopenia in the infant in cases of NATP and ITP.
• Delivery by cesarean section is recommended to prevent CNS bleeding.
• Neonates with severe thrombocytopenia (platelet counts 20,000/mm3) may be treated with IV immunoglobulin or corticosteroids or both until the period of thrombocytopenia remits.
• If necessary, infants with NATP may receive washed maternal platelets.

• A common disorder in children that usually follows an acute viral infection.
• Childhood ITP is caused by an antibody (IgG or IgM) that binds to the platelet membrane. The condition results in splenic destruction of antibody-coated platelets.

Clinical Manifestations

• Young children typically exhibit ITP 1 to 4 weeks after viral illness, with abrupt onset of petechiae, purpura, and epistaxis.
• The thrombocytopenia usually is severe.
• Significant adenopathy or hepatosplenomegaly is unusual, and the RBC and WBC counts are normal.

Laboratory Diagnosis

• Based on clinical presentation and the platelet count and often does not require a bone marrow examination.
• If atypical findings are noted, however, marrow examination is indicated to rule out an infiltrative disorder (leukemia) or an aplastic process (aplastic anemia).
• Examination of the bone marrow reveals increased megakaryocytes and normal erythroid and myeloid elements.

Treatment and Prognosis

• Therapy does not affect the long-term outcome of ITP but is intended to increase the platelet count acutely.
• For clinical bleeding or severe thrombocytopenia (platelet count <20,000/mm3), therapeutic options include
• prednisone, 2 to 4 mg/kg/24 hours for 2 weeks;
• IV immunoglobulin, 1 g/kg/24 hours for 1 to 2 days; or
• IV anti-D (WinRho SD), 50 to 75 μg/kg/dose for Rh-positive individuals.
• Splenectomy is indicated in acute ITP only for life-threatening bleeding.
• Approximately 80% of children have a spontaneous resolution of ITP within 6 months after diagnosis.
• Serious bleeding, especially intracranial bleeding, occurs in less than 1% of patients with ITP.
• ITP that persists for 6 to 12 months is classified as chronic ITP.
• Repeated treatments with IV immunoglobulin or IV anti-D or high-dose pulse steroids have been effective in delaying the need for splenectomy.