Ch 30 Alterations of hemo fxn in children

• Blood cell counts in infants rise above adult levels at birth and gradually decline.
• The immediate rise is due to accelerated hematopoiesis during fetal life and birth trauma.
• Immature erythrocytes and leukocytes decrease within the first 2-3 months of life.

Normal Hemoglobin/Hematocrit (H/H) Values in Infants

• Cord blood: 16.8/55
• 2 weeks: 16.5/50
• 3 months: 12/36
• 6 months to 6 years: 12/37
• 7 years to 12 years: 13/38
• Adults (females to males): 14-16/42-47

Hemolytic Disease of the Newborn (HDN)

• Acquired congenital hemolytic anemia, also called "erythroblastosis fetalis”.
• Alloimmune disorder where maternal antibodies attack fetal erythrocytes due to antigenic incompatibility.
• Fetal erythrocytes bound to maternal antibodies are removed by phagocytosis, usually in the spleen.

Pathophysiology of HDN

• Maternal-fetal incompatibility if they differ in ABO type or if the fetus is Rh+ and the mother is Rh-.
• A antigen forms if the mother's blood is O or B.
• B antigen forms if the mother's blood is O or A.
• HDN results if the mother has preformed antibodies against fetal erythrocytes or produces them upon exposure.
• Sufficient IgG antibodies cross the placenta and enter fetal blood.
• IgG binds with enough fetal erythrocytes to cause hemolysis or splenic removal.
• IgM antibodies against the ABO antigen do not cross the placenta and do not cause HDN.
• Anti-Rh antibodies form after exposure to incompatible Rh-positive erythrocytes.
• Antibodies against Rh antigen are IgG and cross the placenta easily.
• IgG-coated fetal erythrocytes are destroyed by mononuclear phagocytes in the spleen, leading to anemia.
• Erythropoiesis accelerates, releasing erythroblasts into the bloodstream ("erythroblastosis fetalis").
• Unconjugated bilirubin is transported across the placenta to the mother.
• Hyperbilirubinemia occurs after birth because the placenta is no longer available for bilirubin excretion.
• Rh incompatibility is more likely to cause severe anemia, death in utero, or CNS damage.
• Hydrops fetalis involves stillborn fetuses due to anemia in utero and can result in spontaneous abortion as early as 17 weeks.

Etiology of HDN

• Occurs if fetal erythrocytes have antigens different from maternal erythrocytes.
• Most cases are due to ABO incompatibility.
• Types include A, B, or O and the Rh antigen D (positive if present, negative if absent).
• Prevalence is 1/10 cases of ABO incompatibility, affecting subsequent fetuses (antibody produced with first).

Clinical Manifestations of HDN

• Mild HDN presents with slight pallor, spleen, and liver enlargement.
• Severe anemia is indicated by pronounced pallor, splenomegaly, and hepatomegaly, predisposing the neonate to cardiovascular failure and shock.
• Life-threatening Rh incompatibility is rare due to testing and Rh immune globulin use.

Diagnosis of HDN

• Includes the Coombs test.
• Indirect Coombs test measures antibodies in the mother's circulation.
• Direct Coombs test measures antibodies bound to fetal erythrocytes.
• Diagnostic measures include maternal antibody titers, fetal blood sampling, amniotic fluid spectrophotometry, and ultrasound fetal assessment.

Treatment of HDN

• Rh immune globulin must be given to the mother after the birth of each Rh-positive baby and after miscarriages.
• Prevention is key.
• RhoGAM is a preparation of antibody against Rh antigen D, administered within 72 hours of exposure to Rh-positive erythrocytes.
• RhoGAM ensures the mother does NOT produce antibodies against the D antigen.
• The mother should avoid transfusions with Rh-positive blood.
• Given prophylactically at 28 weeks' gestation to Rh-negative women with Rh-positive partners.
• Exchange transfusions replace the neonate's blood with Rh- negative blood within 24 hours of extrauterine life.
• Phototherapy reduces the toxic effects of unconjugated bilirubin (420-470 nm).

Complications of HDN

• Icterus neonatorum (neonatal jaundice) results from continued neonatal erythrocyte destruction.
• Kernicterus involves bilirubin deposits in the brain, which leads to cerebral damage, and possibly death.
• Surviving infants can develop cerebral palsy, developmental delay, or high-frequency deafness.
• Kernicterus is caused by toxic, unconjugated bilirubin deposition in brain cells.
• Kernicterus occurs when maternal antibodies remain post birth and lead to erythrocyte destruction.

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

• G6PD is an inherited, X-linked recessive disorder, most fully expressed in homozygous males.
• Present in 10% of blacks and more common in Sephardic Jews, Greeks, Iranians, Chinese, Filipinos, and Indonesians.

Pathophysiology of G6PD Deficiency

• G6PD is an enzyme that protects erythrocytes from injury caused by drugs, fava beans, hypoxemia, infection, fever, or acidosis.
• Oxidative stressors damage hemoglobin and erythrocyte membranes.
• Hemoglobin is oxidized, leading to precipitation of insoluble hemoglobin (Heinz bodies) in the cell which causes hemolysis.

Etiology of G6PD Deficiency

• G6PD is an inherited, X-linked recessive disorder.
• In Asian and Mediterranean infants, G6PD deficiency is likely associated with icterus neonatorum.

Clinical Manifestations of G6PD Deficiency

• The most common indication of G6PD deficiency is acute hemolytic anemia.
• Fava beans cause severe hemolytic reactions in infants.
• Signs and symptoms of hemolytic episodes include pallor, icterus, dark urine, back pain, shock, cardiovascular collapse, and death.
• Between such episodes, children's erythrocyte survival and anemia are normal.

Diagnostics and Treatment of G6PD Deficiency

• Reduced G6PD activity confirms diagnosis.
• Perform laboratory evaluation shortly after a crisis.
• A late-rising indirect bilirubin level in infants may indicate G6PD deficiency.
• Prevention of hemolysis is the most important therapeutic measure.
• Males from high-risk groups should be tested before administration of oxidative drugs.
• Supportive treatment includes blood transfusion and oral iron therapy, with spontaneous recovery generally following treatment.

Sickle Cell Disease (SCD)

• SCD is characterized by abnormal hemoglobin S (Hb S) within erythrocytes, and is caused by a genetic mutation replacing glutamic acid with valine.
• SCD is inherited as an autosomal recessive disorder.
• Sickle cell anemia (homozygous form) is most severe.
• Sickle cell-thalassemia disease and sickle cell-Hb C disease are heterozygous forms.
• Sickle cell trait involves inheriting Hb S from one parent and normal hemoglobin (Hb A) from the other, which rarely has clinical manifestations.
• All forms are lifelong.
• SCD has a tendency to occur in people from central Africa, Near East, Mediterranean, and parts of India.
• The sickle cell trait may provide protection against lethal forms of malaria.
• Deoxygenation is probably the most important variable in determining occurrence of sickling.
• Stiff, sickled erythrocytes cause plugged blood vessels, which result in vascular occlusion, pain, and organ infarction.
• These cells also undergo hemolysis or become sequestered in the spleen, causing blood pooling and infarction.
• The anemia that follows triggers erythropoiesis in the marrow and liver.
• Sickling can be triggered by decreased oxygen tension, increased hydrogen ion concentration, increased plasma osmolality, decreased plasma volume, and low temperature.

Clinical Manifestations of SCD

• A chronic disease with acute exacerbations.
• SCD affects RBCs that supply O2 to all cells of the body.
• General manifestations are like those of hemolytic anemia: pallor, fatigue, jaundice, and irritability, sometimes accompanied by acute manifestations called crises.
• Four types of crises: vaso-occlusive, aplastic, sequestration, and hyperhemolytic.

Vaso-occlusive Crisis (Thrombotic Crisis)

• Sickling in microcirculation, obstruction leads to vasospasm and the halting of blood flow.
• Usually lasts 4 to 6 days.
• Symptoms include: symmetric painful swelling of hands and feet (hand-foot syndrome), swelling of large joints, priapism, abdominal pain, and strokes.

Aplastic Crisis

• A transient cessation in RBC production leads to acute anemia.
• Usually occurs after viral infection.

Sequestrian Crisis

• Pooling of blood in liver and spleen, only in young children.
• Mortality rates up to 50%.
• Treatment includes spleen removal (after age 5).

Hyperhemolytic Crisis

• Accelerated RBC destruction.
• Characterized by anemia, jaundice, and reticulocytosis.

Diagnosis and Treatment of SCD

• SCD is diagnosed by a sickle solubility test of peripheral blood.
• Hemoglobin electrophoresis provides the amount of Hb S in erythrocytes.
• Prenatal diagnosis is possible via chorionic villus sampling and amniotic fluid sampling.
• Management involves aggressive treatment of fever, early diagnosis of acute chest syndrome, red blood cell transfusions and pain management.

Complications of SCD

• Acute chest syndrome: pulmonary infiltrate, chest pain, temperature > 38.5C, tachypnea, wheezing, and cough.
• Glomerular disease: damage to glomeruli, leading to proteinuria and potential kidney failure.
• Cholecystitis: inflammation of the gallbladder from gallstone blockage.

Thalassemias

• Thalassemias are hereditary hypochromic anemias caused by genetic defects that decrease hemoglobin chain synthesis.
• Classified as inherited autosomal recessive disorders that impair production of alpha or beta chains of Hb A.
• Beta-thalassemia involves slowed or defective synthesis of the beta-globin chain and is common in Greeks, Italians, Arabs, and Sephardic Jews.
• Alpha-thalassemia involves the alpha chain and is most common in Chinese, Vietnamese, Cambodians, and Laotians.
• Classified as either major or minor and has four forms: Alpha trait, Alpha-thalassemia minor, Hemoglobin H disease and Alpha-thalassemia major
• Severity of disease determined by the number of genetic defects.

Clinical Manifestations of Thalassemias

• Beta-thalassemia minor causes mild to moderate microcytic hypochromic hemolytic anemia, mild splenomegaly, bronze coloring of the skin, it is typically asymptomatic
• Beta-thalassemia major results in cardiovascular burden, hepatosplenomegaly, bone marrow hyperplasia; is life threatening
• Alpha-thalassemia has varying forms from mild to life-threatening or fatal

Diagnosis and Treatment of Thalassemias

• Thalassemias is based on are diagnosis based on familial disease history, clinical manifestations and blood tests
• Alpha-thalassemia major and beta-thalassemia major are life threatening
• Thalassemia minor does not require specific treatment.
• Thalassemia major is aimed at prolonging life with treatment involving frequent blood transfusions, chelation therapy and possible splenectomy

Hemophilia/Bleeding Disorders

• Congenital deficiencies of clotting factors VIII, IX, and XI, account for 90% to 95% of hemorrhagic bleeding disorders.

Types of Hemophilia

• Hemophilia A is caused by factor VIII deficiency, it is the most common and inherited as an X-linked recessive trait.
• Hemophilia B (Christmas disease) is caused by factor IX deficiency and is also X-linked.
• Hemophilia C is caused by (factor XI deficiency) which is an autosomal recessive disease and occurs in men and women equally.
• Von Willebrand disease results from an inherited autosomal dominant trait.

Clinical Manifestations and Diagnostics of Hemophilia

• Children with severe hemophilia usually start to bleed at different ages.
• Diagnosed when they become mobile or 3 to 4 years old.
• Adequacy of phase III should be determined first.
• Phase Three assessed by thrombin time
• Activated partial thromboplastin time (aPTT)
• Prothrombin consumption time

Treatment of Hemophilia

• Cryoprecipiate is used to treat individuals with hemophilia.
• Recombinant antihemolytic factor plasma/albumin-free method is a product used in the prevention and control of hemophilia.
• Primary prophylaxis involves regular infusions of factor VIII or IX.

Antibody-Mediated Hemorrhagic Disease

• Idiopathic thrombocytopenic purpura involves antiplatelet antibodies binding to platelet membranes, causing platelet sequestration and destruction and usually occurs after a viral infection.
• Autoimmune vascular purpura: Antibody-mediated injury of blood vessel walls, typically arterioles and capillaries