Paediatrics Marrow Pg 241-250 (Hematology)

Bleeding Disorders

• Normal hemostasis requires blood vessels, platelets, and clotting factors.
• Vascular etiologies for bleeding disorders include:
  • Vasculitis (e.g., Henoch-Schönlein purpura)
  • Scurvy (vitamin C deficiency)
  • Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu syndrome)

Platelet vs Coagulation Disorders

• Platelet disorders typically cause mucocutaneous bleeding, petechiae, and multiple, small ecchymoses.
• Coagulation disorders predominantly lead to deep bleeding in muscles and joints (hemarthrosis) and single, large ecchymoses.
• Patients with platelet disorders will experience bleeding after minor trauma, while coagulation disorders may result in delayed bleeding after surgery.

Immune Thrombocytopenic Purpura (ITP)

• Pathogenesis:
  • Molecular mimicry:
    • Viral infections, particularly in children aged 1-7, can trigger autoantibody production against GP IIb/IIIa receptors on platelets.
    • Antibody-coated platelets enter the spleen and are recognized by Fc receptors on splenic macrophages leading to lysis of platelets.
    • This results in autoimmune thrombocytopenia.
  • Bone marrow Compensation: Megakaryocyte production increases in response to platelet loss.

Sickle Cell Anemia

• Inheritance: Autosomal recessive

• Incidence: High incidence in tribal populations of Madhya Pradesh and Maharashtra, India.

• Pathogenesis:

  • Mutation: Mutation in the gene for β-globin chain of hemoglobin.
  • Amino Acid Substitution: Glutamate is replaced by valine at the 6th position of the β-globin chain.
  • HbS Production: Defective HbS is produced (normal Hb: HbA).

• RBCs with HbS:

  • Clinical Features: Hypoxia, dehydration, fever, and metabolic acidosis can trigger sickling.
  • Sickling: Repeated sickling leads to fragile red blood cells and hemolysis.

• Clinical Features (Sickle Cell Anemia):

  • Onset: Symptoms manifest after 6 months of age due to the protective effect of HbF (fetal hemoglobin) during the first 6 months.
  • Symptoms: Icterus, pallor, and characteristic painful vaso-occlusive crises.
  • Dactylitis/Hand and Foot Syndrome: Swelling of fingers and toes typically presenting in infancy.

• Management:

  • Supportive: Most episodes are self-limiting, and implicated drugs should be avoided.
  • Diagnostic Test: Enzyme assay in RBCs confirms decreased enzyme levels.

β-Thalassemia

• Mode of Inheritance: Autosomal recessive

• Types:

  • Reduction or absence of β-globin chain synthesis.
  • Normally, alleles code for β-globin chain.
  • Key:
    • β: Normal
    • β⁺: Decreased production
    • β⁰: No production

• Genotype & Severity:

  Genotype	Name	Severity
  β/β	Normal	Asymptomatic
  β/β⁺	β-Thalassaemia trait (mild)	Mild to moderate
  β+/β⁺		Mild to moderate (β+/β° > β+/β+)
  β+/β⁰	β-Thalassaemia intermedia
  β⁰/β⁰	β-Thalassaemia major/cooley's anemia (most severe)	Severe (Transfusion every 3-4 weeks)

• Pathophysiology & Clinical Features:

  • α-Chain Accumulation: Accumulation of α-chains in RBCs leading to cell instability and early destruction.
  • Ineffective Erythropoiesis:
  • Severe Anemia: Transfusion-dependent anemia.
  • Extramedullary Hematopoiesis:
    • Hepatosplenomegaly
    • Skull involvement.
  • Note: α & β chains are typically produced in a 1:1 ratio.

• Clinical Features:

  • Frontal bossing
  • Depressed nasal bridge
  • Maxillary prominence
  • Dental malocclusion
  • Thalassemic facies
  • Prominent vertical trabeculae
  • Hair-on-end appearance

• X-Ray (Hair-on-End Appearance): An X-ray of the skull demonstrates a characteristic "hair-on-end" appearance.

Investigations (Hematology)

• Peripheral Smear:

  • Nucleated RBCs
  • Microcytic
  • Hypochromic RBCs (Central pallor > 1/3rd)

• Hemoglobin Electrophoresis: Initial diagnostic test.

• High-Performance Liquid Chromatography (HPLC): Gold standard test.

• Management (Supportive):

  • Blood transfusions every 3-4 weeks.
  • Leukocyte-depleted/irradiated blood products reduce the risk of allergic reactions.
  • Pre-transfusion target Hb 9-10 g/dL: Reduces skeletal deformities and promotes growth.

• Management (Curative): Hematopoietic stem cell transplant.

Complications of Iron Overload (β-Thalassemia)

• Risk: Due to repeated transfusions (over 1 year of transfusion), iron overload is a significant concern.

• Morbidity & Mortality: Major cause of morbidity and mortality (cardiotoxicity).

• Organ Damage: Liver, spleen, and heart.

• High Transferrin Saturation:

  • Decreased bacteriostatic properties of lactoferrin.
  • Increased risk of infections (most common: Yersinia enterocolitica).

• Investigations:

  • Serum ferritin > 1000 pg/L.
  • MRI (Ra or Ra* weighted Ta-weighted cardiac MRI and Liver MRI: Best)

• Management:

  • Iron chelators:
    • Deferasirox (Oral): Preferred; Causes mild GI disturbances.
    • Deferoxamine (s.c): Side effects: Ototoxicity & retinal toxicity.
    • Deferiprone (Oral): Side effects: Neutropenia & cartilage damage.

Sickle Cell Anemia - Additional Information

• Acute Chest Syndrome: Fever and breathing difficulty, resembling pneumonia. Chest X-ray shows new-onset infiltrates.
• Stroke Episodes: Can occur due to sickling of cells in the brain.
• Autosplenectomy: Repeated infarcts in the spleen lead to autosplenectomy by age 6, resulting in functional hyposplenism and recurrent infections by encapsulated bacteria.
• Venous Blockade & Pallor: Venous blockade causes acute pooling of blood, leading to a 22% reduction in hemoglobin, resulting in pallor and shock.
• Aplastic Crisis: Pancytopenia precipitated by parvovirus B19 infection.

Investigations (Sickle Cell Anemia)

• Peripheral Smear: Sickled RBCs.

• Screening Test:

  • Sickling test: Induction of sickling by adding 2% sodium metabisulphite.

• Hb Electrophoresis: Initial, best diagnostic test.

• High-Performance Liquid Chromatography (HPLC): Gold standard test for detecting and quantifying HbS.

• Sickle Cell Trait: HbA + HbS – Less severe manifestations.

Management (Sickle Cell Anemia)

• Good hydration
• Analgesics for pain episodes
• PRBC transfusions: Used for Aplastic crisis, sequestration crisis, and to increase blood's oxygen carrying capacity.
• Exchange transfusion: Used for acute chest syndrome and stroke to remove HbS from circulation. Goal: Hbs concentration < 30%.

Acute ITP

• Age: 1-7 years

• Viral Infection Trigger: Viral infection 1-4 weeks prior to onset.

• Clinical Features:

  • Sudden onset of mucocutaneous bleeds (petechiae > epistaxis, oral oozing).
  • Child generally appears well.
  • Rare:
    • Gastrointestinal (GI) bleeds
    • Hematuria
    • Central nervous system (CNS) bleeds (Fatal).

• Lymphadenopathy & Splenomegaly: Usually not seen in acute ITP; If present, evaluate for a different underlying cause, such as leukemia.

Investigations (Acute ITP)

• Blood Count:
  • Peripheral smear: Normal-sized and large (young platelets) due to bone marrow compensation.
  • Bone marrow aspiration: Increased megakaryocytes.

Management (Acute ITP)

• Supportive Care: Majority of cases are self-limiting.

• Treatment Decision: Based on clinical symptoms (organ bleeds/increased number of bleeds) and not solely on platelet counts.

• Treatment Options:

  • IV Immunoglobulins (best): Reduces macrophage activity and platelet destruction.
  • Steroids (Prednisolone): Increases platelet production.
  • Platelet Transfusions: Only used for life-threatening bleeds.

Other Causes of Thrombocytopenia

• Aplastic anemia
• Marrow infiltration (Leukemia/storage disorders)
• Connective tissue disorders (e.g., SLE)
• Infections: Parvovirus, EBV, Varicella, Rubella, mumps
• Drugs:
  • Heparin
  • Valproate, Phenytoin
  • NSAIDs
  • Penicillins & Cephalosporins

Congenital Hemolytic Anemia

• Investigations:
  • Peripheral Smear: Lack of central pallor in spherocytes due to loss of surface area during shape change and cellular dehydration.
  • Red blood cell indices: ↑MCHC is characteristic.
  • Screening Tests:
    • Osmotic Fragility: Increased permeability to Na+ in spherocytes.
    • Incubated osmotic fragility: Blood is incubated at 37°C for 24 hours to improve test sensitivity. Osmotic fragility is also seen in other hemolytic disorders.
  • Confirmatory Tests:
    • Flow cytometry: Bending of eosin-5-maleimide (EMA) to proteins.
    • Molecular testing: Deletion of mutations in RBCs.

Management (Congenital Hemolytic Anemia)

• Lifelong folic acid supplementation: Given for megaloblastic erythropoiesis due to chronic hemolysis and should be administered to all children with chronic hemolytic anemia.
• Splenectomy:
  • Best treatment modality: Decreases lysis, increases RBC lifespan, and reduces anemia severity.
  • Laparoscopic partial splenectomy is preferred.
  • Concomitant cholecystectomy if gallstones are present.

Treatment Options:

• Fresh Frozen Plasma (FFP):
• Cryoprecipitate: Contains Factor VIII & fibrinogen. Useful only in Hemophilia A.

Complications of Treatment (Inherited Bleeding Disorders)

• Antibodies to clotting factor: Most serious complication, leading to patients stopping responding to factor replacement therapy.

Treatment (Inherited Bleeding Disorders)

• Bypass agents: Used to bypass the defective clotting factor in the cascade.

Bypass Agents:

• Recombinant Factor Vila
• Activated Prothrombin Complexes (APCS)/ Factor VIII Inhibitor Bypass Activity (FEIBA)

Von Willebrand Disease (VWD)

• Most common inherited bleeding disorder worldwide
• Inheritance: Mostly autosomal dominant.

Functions of von Willebrand Factor (vWF)

• Factor VIII Binding: Binds to factor VIII, increasing its half-life.
• Platelet-Collagen Bridge: Acts as a bridge between platelets and subendothelial collagen.

Non-Factor Type (Treatment)

• Emicizumab: Monoclonal antibody to factor VIII (Hemophilia A only).

Types of VWD

Consequences of Splenectomy

• Active Space: The absence of splenic macrophages, which normally remove old or damaged red blood cells, increases the risk of infection by encapsulated bacteria due to a lack of phagocytic function.
• Risk of Infection: Especially in children less than 6 years of age.
• Immunization: Post-splenectomy, patients require immunizations with encapsulated organisms to protect against infections.
• Penicillin Prophylaxis: Penicillin prophylaxis for 2 years post-splenectomy is recommended.

G6PD Deficiency

• Most Common RBC Enzyme Deficiency
• Inheritance: X-linked recessive.
• Prevalence: Commonly seen in Africans, Mediterranean populations, and Asians.

Pathophysiology (G6PD Deficiency)

• HMP Shunt: Glucose-6-phosphate is converted to 6-phosphoglycerate via G6PD, generating NADPH, which is required to maintain reduced glutathione levels.
• Reduced Glutathione: Levels of reduced glutathione decrease, leading to increased oxidative stress and hemolysis.

Clinical Features (G6PD Deficiency)

• Varied Onset:
  • Early: Neonatal jaundice.
  • Late: Episodic hemolysis.
• Risk Factors for Episodic Hemolysis:
  • Fever
  • Drugs: (Usually begin 2-3 days after drug exposure and are self-limiting):
    • Primaquine
    • Nitrofurantoin
    • Sulfonamides
  • Fava Beans

Investigations (G6PD Deficiency)

• Peripheral Smear:
  • Heinz bodies
  • Decreased Hb
  • Bite cells

Inherited Bleeding Disorders: Hemophilia

• Gene Defect: Clotting factor defect leading to delayed clot formation and bleeding.
• Bleeding Manifestations: Hemarthrosis, muscle hematomas, and various types of bleeding.

Types of Hemophilia:

Clinical Features (Hemophilia)

• Hemarthrosis: Bleeding into a joint.
• Hallmark Feature: Hemarthrosis is a hallmark feature of hemophilia.
• Most Common Joint Affected: Knee > elbow, ankle.
• Target Joint: Repeated bleeds into the same joint.
• Fibrosis: Restriction of joint movements is a common cause of morbidity.

Classification (Hemophilia)