McCance 31 Book

• This chapter explains fetal/neonatal hematopoiesis and postnatal blood changes as a base for understanding childhood blood disorders.
• Focus: diseases affecting erythrocytes(acquired & inherited), coagulation/platelet disorders (inherited hemorrhagic diseases and antibody-mediated hemorrhagic diseases), and leukocyte disorders (leukemia and lymphomas).

Fetal and Neonatal Hematopoiesis

• Erythrocyte production starts in the yolk sac vessels when the embryo outgrows simple diffusion for oxygen.
• At approximately 2 weeks of gestation circulating erythrocytes become crucial for tissue oxygen delivery.
• Around week 8, erythrocyte production shifts to the liver sinusoids; leukocytes and platelets also begin production in the liver and spleen.
• Liver erythropoiesis peaks at approximately 4 months, then declines but persists through gestation.
• By month 5, hematopoiesis starts in the bone marrow and expands until hematopoietic marrow fills the bone marrow space.
• At delivery, bone marrow becomes the primary hematopoiesis site.
• In neonates/infants, hematopoietic marrow fills bones of the axial skeleton (skull, vertebrae, ribs, sternum), long bones, and intramembranous bones.
• Fatty (yellow) marrow gradually replaces hematopoietic marrow in bones.
• Hematopoietic tissue retreats centrally to the vertebrae, ribs, sternum, pelvis, scapulae, skull, and proximal ends of the femur and humerus during childhood.
• Erythrocyte production can increase up to eight times the normal level in hemolytic diseases due to erythropoietin stimulating the hematopoietic marrow.
• Hematopoietic marrow expands from long bone ends toward the middle, replacing fatty marrow.
• Blood cell production can occur outside of the marrow cavities, particularly in the liver and spleen, because children's bony cavities are already filled with red marrow which is called Extramedullary hematopoiesis .
• Liver and spleen enlargement is more pronounced in children with hemolytic disease.
• Erythrocytes increase in number and hemoglobin content during gestation (especially in the first two trimesters) followed by hematocrit level increase.
• Erythrocyte count more than triples while their size decreases by the end of gestation.

Hemoglobin Synthesis

• Embryonic hemoglobins (Gower 1, Gower 2, and Portland) and fetal hemoglobin (HbF) consist of two α and two γ polypeptide chains.
• Adult hemoglobins HbA and HbA2 are composed of two α and two β chains
• An unknown regulatory mechanism promotes γ-chain synthesis and inhibits β- and δ-chain synthesis in utero, resulting in embryonic or fetal hemoglobin production.
• After birth, γ-chain synthesis is inhibited, whereas β- and δ-chain synthesis is facilitated, resulting in adult hemoglobins production.
• Fetal hemoglobin has a greater affinity for oxygen than adult hemoglobin because it interacts less readily with 2,3-diphosphoglycerate (2,3-DPG).
• Decreased 2,3-DPG effects enable fetal blood to transport oxygen despite a low-oxygen uterine environment.
• Increased oxygen affinity enables HbF to bind with maternal oxygen in the placental circulation.
• During the 1st trimester, nearly all hemoglobin in the fetus is embryonic, but some HbA can be detected.
• Disorders of adult hemoglobin (sickle cell anemia and thalassemia major) can be identified as early as 16 to 20 weeks of gestation.
• HbF constitutes 90% of the total in the 6-month fetus, then declines.
• At birth, neonatal hemoglobin consists of 70% HbF, 29% HbA, and 1% HbA2.
• Normal adult hemoglobin percentages are established between 6 and 12 months of age.

Postnatal Changes in Blood

• Blood cell counts rise higher than adult levels at birth, then gradually decline throughout childhood.
• Table 31.1 lists normal ranges during infancy and childhood.
• The immediate rise in values is due to accelerated hematopoiesis during fetal life, increased cell numbers from birth trauma, and umbilical cord cutting.
• Birth events are accompanied by immature erythrocytes and leukocytes (particularly granulocytes) in peripheral blood.
• Immature blood cell numbers decrease as the infant develops over the first 2 to 3 months of life.
• Average blood volume in full-term neonates is 85 mL/kg of body weight vs premature infants having a larger blood volume of 90 to 100 mL/kg of body weight.
• Blood volume relative to body weight decreases during the first few months, with a child’s average blood volume being 75 to 77 mL/kg by age 3.

Erythrocytes

• The hypoxic intrauterine environment stimulates erythropoietin production in the fetus, accelerating fetal erythropoiesis and leading to polycythemia in newborns.
• After birth, oxygen from the lungs saturates arterial blood, increasing oxygen delivery to the tissues.
• Erythropoietin levels and the rate of blood cell formation decrease in response to the change from placental to pulmonary oxygen supply during the first few days of life.
• High numbers of immature erythrocytes (reticulocytes) in the peripheral blood of full-term neonates reflect very active rate of fetal erythropoiesis.
• Reticulocyte number decreases abruptly during the 1st few days after birth, associated with decreased erythropoietin production.
• Elevated reticulocyte count after the 1st week of life is rare.
• Decrease in extramedullary hematopoiesis also occurs.
• Erythrocyte count drops for 6 to 8 weeks after birth in the peripheral blood because the rate of erythrocyte destruction exceeds production.
• Erythrocyte life span: 60 to 80 days in full-term infants, 20 to 30 days in premature infants and 120 days in children and adolescents (same as adults)
• Postnatal decrease in hemoglobin/hematocrit values is more marked in premature infants than in full-term infants.
• Hemoglobin, hematocrit, and RBC count values gradually rise in the preschool and school-age child, diverging between males and females during adolescence.
• Hemoglobin level increase continues into early puberty in females (then stabilizes) while in males, it keeps pace with growth and maturation and eventually surpasses that of females due to androgen secretion.
• Neonate erythrocytes consume greater quantities of glucose than adult erythrocytes.
• Enzymes regulating glucose consumption are increased in neonate erythrocytes, increasing glycolysis rate.

Leukocytes and Platelets

• Lymphocytes of children tend to have more cytoplasm and less compact nuclear chromatin than adult lymphocytes, possibly due to more frequent viral infections.
• Minor infections or immunizations may result in lymphocyte changes.
• Lymphocyte count is high at birth, continues to rise in some infants during the first year, then steadily declines throughout childhood/adolescence to reach adult levels.
• The neutrophil count peaks at 6 to 12 hours after birth in healthy neonates then declines over the next few days, with female neonates having slightly higher counts than males.
• After 2 weeks of age, neutrophil counts fall to within or below normal adult ranges with white children having slightly higher counts than black children.
• Eosinophil counts are elevated in the first year of life relative to children, teenagers, or adults.
• Monocyte counts are elevated through the preschool years, then decrease to adult levels.
• No relationship between age and basophil count has been found.
• Platelet counts in full-term neonates are comparable to adult platelet counts, remaining so throughout infancy and childhood.

Disorders of Erythrocytes

• Anemia is the most common blood disorder in children, resulting from ineffective erythropoiesis or premature erythrocyte destruction.
• Insufficient erythropoiesis is commonly caused by iron deficiency from insufficient dietary intake or chronic blood loss.
• Hemolytic anemias of childhood include disorders resulting from erythrocyte intrinsic abnormalities or damaging extra-erythrocytic factors
• Hemolytic anemias can be inherited, congenital, or both.
• Hemolytic disease of the fetus and newborn (HDFN) is the most dramatic form of acquired congenital hemolytic anemia, an alloimmune disorder where maternal and fetal blood are antigenically incompatible.
• Inherited hemolytic anemia results from erythrocyte intrinsic defects, leading to erythrocyte destruction by the mononuclear phagocyte system.
• Structural defects manifest as abnormal red blood cell size/plasma membrane structure abnormalities (spherocytosis).
• Intracellular defects: enzyme deficiencies (G6PD deficiency) and hemoglobin synthesis defects (sickle cell disease or thalassemia).

Acquired Disorders

• Iron deficiency anemia, hemolytic disease, infectious disease related anemias

Inherited Disorders

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency, hereditary spherocytosis, sickle cell disease, and thalassemias

Iron Deficiency Anemia

• Critical for normal brain development in children (the damage from periods of iron deficiency anemia (IDA) in children is irreversible)
• It’s the most common nutritional disorder worldwide, highest incidence between 6 months and 2 years of age.
• Common in the United States, higher prevalence found in toddlers, adolescent girls, and women of childbearing age, and causes clinical manifestations mostly related to inadequate hemoglobin synthesis.
• Risk factors: Socioeconomic factors affect nutrition; incidence not related to gender or race.
• Causes: Dietary insufficiencies, absorption problems, blood loss, and increased iron requirement.
• Inadequate intake is the most common cause of IDA during the first few years of life and blood loss is the most common cause during childhood and adolescence, and for adults in the Western world
• Chronic IDA from occult (hidden) blood loss may be caused by a gastrointestinal lesion, parasitic infestation, or hemorrhagic disease.
• Infants/young children with IDA may have chronic intestinal blood loss due to heat-labile protein exposure in cow’s milk, thus causing an inflammatory gastrointestinal reaction damaging mucosa with diffuse microhemorrhage.
• Growing evidence indicates that cellular components of both innate and adaptive immunity play significant roles during the pathogenesis of cow’s milk allergy.
• Dietary lack is not common in developed countries where iron is in the readily absorbed form from heme that comes from meat.
• Bioavailability of iron from breast milk is higher than that from cow’s milk.
• Impaired absorption is found in chronic diarrhea, fat malabsorption, and celiac disease.
• Genetic polymorphisms may alter iron absorption in cases of refractory IDA with a familial component.
• Children in developing countries are often affected by chronic parasite infestations that result in blood and iron loss greater than dietary intake.
• Treatment of helminth infections results in improvement in appetite, growth, and in the anemia.
• Recent New areas of investigation: IDA in overweight children and the association of H. pylori infection with IDA.

Pathophysiology of Iron Deficiency Anemia

• Deficiency of iron produces a hypochromic-microcytic anemia.
• Progressive depletion of blood and decrease in serum levels of ferritin/transferrin saturation then leads to lowering of hemoglobin and hematocrit values.
• Adaptive increase in bone marrow red blood cell activity may prevent anemia development in early stages.
• Anemia develops when iron stores are depleted alongside important laboratory indicators.

Clinical Manifestations of Iron Deficiency Anemia

• Mild anemia symptoms (lethargy, listlessness) not clearly evident in infants and young children, so parents may not notice changes until moderate anemia develops.
• Nonspecific indications: general irritability, decreased activity tolerance, weakness, and lack of interest in play.
• In mild to moderate IDA (hemoglobin level of 6 to 10 g/dL), compensatory mechanisms such as increased 2,3-DPG and a shift of the oxyhemoglobin dissociation curve, may be effective that few clinical manifestations are apparent.
• Pallor, tachycardia, and systolic murmurs often manifest when hemoglobin level falls below 5 g/dL.
• Clinical manifestations of Chronic IDA: splenomegaly, widened skull sutures, decreased physical growth, developmental delays, and pica (eating non-food substances).
• Consequences of IDA: altered neurologic and intellectual function, especially involving attention span, alertness, and learning ability.

Evaluation and Treatment of Iron Deficiency Anemia

• Laboratory tests confirm the diagnosis of IDA and include measurements of hemoglobin, hematocrit, serum iron, ferritin, and the total iron-binding capacity.
• The approach is similar to adults, requiring a thorough history of present/ dietary habits + physical exam
• Oral administration of simple ferrous salts usually is satisfactory, and additional vitamin C helps promote absorption.
• Liquid iron should be administered through a straw to prevent teeth staining.
• Iron therapy is continued for at least 2 months after erythrocyte indexes have returned to normal to replenish iron stores.
• Dietary modification is required to prevent recurrences of IDA: increase intake of iron-rich foods while restricting cow's milk intake.
• Limiting milk intake makes the child hungrier for other iron-rich foods and prevents gastrointestinal blood loss in children whose anemia is aggravated or caused by inlammatory reactions to proteins in cow’s milk.

Hemolytic Disease of the Fetus and Newborn

• HDFN can occur only if antigens on fetal erythrocytes differ from antigens on maternal erythrocytes.
• Erythrocyte antigenic properties are genetically determined (type A, B, or O, and Rh antigen D).
• Erythrocytes expressing Rh antigen D are Rh-positive; those that do not are Rh-negative(higher frequency in whites (15%) than in blacks (5%), and rare in Asians).
• Maternal-fetal incompatibility exists if mother and fetus differ in ABO blood type or if the fetus is Rh-positive and the mother is Rh-negative.
• ABO incompatibility occurs in about 20% to 25% of all pregnancies, though only 1 in 10 cases results in HDFN.
• Rh incompatibility occurs in less than 10% of pregnancies and rarely causes HDFN in the first incompatible fetus.
• Mother's immune system produces antibodies that affect fetuses of subsequent incompatible pregnancies, with most cases of HDFN caused by ABO incompatibility.
• Anti-Rh antibodies, are formed only in response to the presence of incompatible (Rh-positive) erythrocytes in the blood of an Rh-negative mother.
• ABO incompatibility can cause HDFN because many adults already have anti-A or anti-B antibodies from exposure to certain foods/gram-negative bacteria.

Pathophysiology of Hemolytic Disease of the Fetus and Newborn

• HDFN will result from the following:
  • Mother's blood contains preformed antibodies against erythrocytes or produces antibodies upon exposure to fetal erythrocytes.
  • Sufficient IgG antibodies cross the placenta into fetal blood.
  • IgG binds with sufficient numbers of fetal erythrocytes, causing widespread antibody-mediated hemolysis or splenic removal.
• The first Rh-incompatible pregnancy usually presents no difficulties because very few fetal erythrocytes cross the placental barrier during gestation.
• At birth, when the placenta detaches large numbers of fetal erythrocytes usually enter the mother’s bloodstream.
• Mother produces anti-Rh antibodies (capacity depends on genetics, amount of fetal-to-maternal bleeding, and prior bleeding events).
• Anti-Rh antibodies persist in the bloodstream, and if the next offspring is Rh-positive, the mother’s anti-Rh antibodies can enter the fetus’s bloodstream and destroy erythrocytes.
• IgG-coated fetal erythrocytes are destroyed through extravascular hemolysis, primarily by mononuclear phagocytes in the spleen then causing the fetus anemia with accelerated erythropoiesis, particularly in the liver and spleen.
• Immature nucleated cells (erythroblasts) are released into the bloodstream (erythroblastosis fetalis).
• Degree of anemia depends on antibody concentration/exposure time and fetal compensation ability.
• Bilirubin (formed during hemoglobin breakdown), which is transported across the placenta into the maternal circulation and is excreted by the mother.
• Hyperbilirubinemia (increased bilirubin concentration) occurs in the neonate after birth because excretion of lipid-soluble unconjugated bilirubin through the placenta no longer is possible.
• HDFN effects are more severe in Rh incompatibility than in ABO incompatibility, though ABO typically spontaneously resolves on its own and not life-threatening complications.
• Rh incompatibility is more likely to cause severe anemia, death in utero, or CNS damage though Severe anemia alone can cause death as a result of cardiovascular complications.
• Extensive hemolysis leads to increased unconjugated bilirubin levels where excess bilirubin is deposited in the brain (kernicterus), causing cellular damage/death.
• Fetuses that do not survive anemia in utero usually are stillborn with gross edema called hydrops fetalis (Death can occur as early as 17 weeks of gestation).

Clinical Manifestations of Hemolytic Disease of the Fetus and Newborn

• Mild HDFN: neonates may appear healthy/slightly pale, with slight liver/spleen enlargement.
• Severe anemia is indicated by pronounced pallor, splenomegaly, and hepatomegaly, predisposing to cardiovascular failure/shock.
• Maternal antibodies in neonatal circulation cause continued erythrocyte destruction followed by Hyperbilirubinemia and icterus neonatorum (neonatal jaundice)
• Without replacement transfusions, bilirubin is deposited in the brain, causing kernicterus which produces cerebral damage/death.
• Infants who do not die may have significant developmental delay, cerebral palsy, or high-frequency deafness

Evaluation and Treatment Hemolytic Disease of the Fetus and Newborn

• Routine HDFN evaluation includes the Coombs test
• indirect Coombs measures antibody in the mother’s circulation, indicating fetal risk.
• direct Coombs measures antibody already bound to fetal erythrocytes, confirming antibody-mediated HDFN.
• Diagnostic measures include maternal antibody titers, fetal blood sampling, amniotic fluid spectrophotometry, and ultrasound fetal assessment.
• Prevention is key to avoid severe complications: Rh immune globulin (RhoGAM), an IgG preparation against Rh antigen D (anti-D Ig), is administered within 72 hours of exposure to Rh-positive erythrocytes.
• Injecting anti-D Ig antibodies to prevent her immune system from producing its own anti-Rh antibodies.
• The mother must be given Rh immune globulin injections after the birth of each Rh-positive baby and after a miscarriage.
• Should not receive transfusion containing Rh-positive blood.
• Exchange transfusions (neonate's blood replaced with new Rh-positive blood without anti-Rh antibodies) and phototherapy is instituted during the first 24 hours of extrauterine life to prevent kernicterus.
• Infants are exposed to high-intensity light in the visible spectrum from 460 to 490 nm to lowers the toxic effects of unconjugated bilirubin.
• Light energy converts bilirubin into conjugated isomers that are excreted in the bile and causes autosensitization resulting in oxidation reactions

Anemia of Infectious Disease

• Infections of the newborn may result in hemolytic anemia with clinical manifestations similar to those of HDFN (congenital syphilis, toxoplasmosis, cytomegalic inclusion disease, rubella, coxsackievirus B infection, herpesvirus infection, and bacterial sepsis).
• Exact mechanism of anemia is unclear though it is related to direct erythrocyte membrane/precursor injury by microorganism, or traumatic destruction of erythrocytes during passage through inflamed capillaries.

Anemia in Critically Ill Children

• Anemia is a common occurrence in critically ill children.
• Causes: decreased erythropoietin activity, poor iron use by the body, and blood loss.
• Ongoing discussion: improve outcomes in critically ill children with Transfusion of packed blood products

Inherited Disorders that can cause cause Hemolytic Disease

• Plasma membrane defects accompanied by changes in erythrocyte size or shape and enzymatic abnormalities

Glucose-6-Phosphate Dehydrogenase Deficiency

• G6PD deficiency is an inherited disorder caused by a genetic defect in the RBC enzyme G6PD
• The deficiency occurs most often in tropical and subtropical regions of the Eastern Hemisphere including Europe, Africa, and Asia.
• It is an X-linked recessive disorder, most fully expressed in homozygous males.
• G6PD is responsible for the first step in converting glucose to ribose-5-phosphate, producing NADPH, which helps protect cells from oxidative stress from reactive oxygen species (ROS).
• Common RBC disorder, impacts 200 to 400 million people worldwide.
• Damaged RBCs rupture and break prematurely (hemolysis).

Pathophysiology Glucose-6-Phosphate Dehydrogenase Deficiency

• Deficient enzyme function causes abnormalities that impair RBCs ability to protect themselves against oxidative stress injuries, leading to hemolysis.
• Oxidants cause both intravascular and extravascular hemolysis in G6PD-deficient individuals.
• Therefore, the G6PD deficiency is usually asymptomatic unless one of these exposures occurs.
• G6PD enables erythrocytes to maintain normal metabolic processes despite injury from oxidative stressors: certain drugs (sulfonamides, nitrofurantoins, antimalarial agents, salicylates, or naphthaquinolones), ingestion of fava beans, hypoxemia, infection, fever, or acidosis.
• Infections frequently initiate hemolysis (hepatitis, pneumonia, typhoid fever) whereas Erythrocyte damage begins after intense/prolonged exposure to stressors.

Clinical Manifestations Glucose-6-Phosphate Dehydrogenase Deficiency

• May present as icterus neonatorum in infants.
• Most common clinical manifestation of G6PD deficiency is acute hemolytic anemia, usually after infections or oxidative drugs.
• Hemolytic episodes are defined by pallor, icterus, dark urine, back pain + severe cases of shock/cardiovascular collapse
• Normal erythrocyte survival and no anemia occurs between hemolytic episodes.

Evaluation and Treatment Glucose-6-Phosphate Dehydrogenase Deficiency

• Prevention includes avoiding medications and dietary substances that triggers and includes Reduced G6PD activity in erythrocytes
• Treatment involves Blood transfusions and oral iron therapy.
• Spontaneous recovery generally follows treatment.
• The World Health Organization recommends G6PD testing before antimalarial medications in endemic areas.

Hereditary Spherocytosis

• HS is transmitted in about 75% of cases
• It is an inherited disorder caused by defects in the membrane skeleton of RBCs
• These genes provide proteins for producing RBC membranes.
• The affected proteins include spectrins and ankyrin, and their intrinsic defects in the membrane cause less deformability and increased vulnerability to splenic sequestration and destruction.

Pathophysiology Hereditary Spherocytosis

• HS is intimately involved in the hemolytic process, and spherocytes are relatively rigid
• Proteins in Spherocyte membranes result in shape changes, becoming more spherical instead of flattened disc shape, and rigid; these misshapen cells, or spherocytes, are then removed from circulation and destruction from circulation.
• Circulation of blood to the spleen creates repeated circulation through a metabolic environment that results in sequestration and destruction of spherocytes.

Clinical Manifestations Hereditary Spherocytosis

• Splenomegaly is usually mild, and anemia may be mild/absent depending on the individual’s physiologic compensation but elevated reticulocyte count
• Infant developing signs of hemolytic anemia and hyperbilirubinemia, with mild to severe anemia dependent on age.
• Fever, infection and stress stimulate spleen to destroy more RBCs than usual, worsening anemia in a child with baseline anemia.

Evaluation and Treatment Hereditary Spherocytosis

• Family history + spherocytes detected in peripheral blood smear (spherocytosis),
• elevated reticulocyte count (with or without anemia),
• indirect hyperbilirubinemia, + positive osmotic fragility test = diagnosis determination
• Splenectomy recommended for those children more than 5 years of age with severe disease or symptomatic gallstones

Sickle Cell Disease

• The HbB gene provides instructions for making protein β-globin, where other mutations in HbB can lead to other versions β-globin such as hemoglobin C (HbC) and E (HbE)
• Disease therapies: use HSCT stem cell transplantation (however, infrequently performed, needs significant investigation, chronic transfusion)
• Mutation in β-globin leads to the replacement of glutamate with valine, deoxygenation and oxygenation causing stiffening of the HbS molecule, damaging RBC's die resulting to hemolytic and anemia, and microvascular obstruction = tissue damage resulting in ischemic
• Affects millions of people worldwide, also inherited in autosomal recessive, each parents carrying one copy of gene

Pathophysiology of Sickle Cell Disease

• Most important variable in determining occurrence of sickling is deoxygentation (transit times, intracellular pH) and presence of other types of HB can prevent sickling, unless there is severe hypoxia
• Variables include intracellular dehydration (incr sickling), inflammation in microcirculation (slows transit times b/c blood low sluggish)
• Osmolarity increase (increase water drawn from erythrocytes) therefore it promotes sickling from Hbs content in erythrocytes
• Intravenous fluid is also a contributor in increasing erythrocyte deformability and biomechanical propertie, and low temperatures promote vasoconstriction
• Sickling damages erythrocytes through polymer protrusion via membrane (changes mem structure)> Ca+ influx via ionic flow changes via membrane arrangement

Clinical Manifestations Sickle Cell Disease

• Characterized by chronicity acute exacerbation related to RBC (02 to cell supply throughout body)
• Hypoxia/infarction causes pain at bones, lungs, spleen, liver, and penis.
• Bone alterations manifest through painful hand and feet swelling (hand-foot syndrome/dactylitis)
• Vaso-occlusive crisis may develop spontaneously through infection, exposure to dehydration, acidosis, exposure to cold/ localized hypoxemia and low P02

Evaluation and Treatment Sickle Cell Disease

• In sickle cell disease, test are hemoglobin ELECTROPHORESIS (info HbS amounts) and SICKLE SOLUBILITY (detects HbS in blood)
• Supportive care targets consequences of anemia, preventing crises by fever, hydration, and acidosis corrections
• Aggressive management of fever, anemia, lung issues + transfusions (progressive pneumonia, fat emboli) improves quality of life,
  • vaccines and antibiotic therapy can manage infection/prevent it
• Hydroxyurea can target DNA synthesis inhibiting therefore it reduces proportion of HbS via increase Hbf.
• Counselling for psychological is also beneficial for both client and family

Thalassemias

• Genetic, recessive = impaired synthesis of α/β chains of HbA
• Classified based on severity (major/intermedia) = result of HBB mutations (decrease β-globin chain synthesis) which is classified based on anemia levels
• Alpha trait (deletion HBA1/2 genes
  • trait/minor types are asymptomatic (mild microcytosis)
  • Alpha Thal Major= hydrops fettles= CHF. (usually stillborn & done via chorionic villus).
  • Beta depression= decreased erythropoiesis= anemia (thal minor is beta allele resulting to mild anemia
  • Severe in homozygotes= impaired development)
  • Most genetic studies done= miss sense
• Depress β-chain synthesis, free alpha precipitate causing immature Erythrocyte haemolysis
• B Thal major = Hba absent/ low with HF/A2 levels high

Evaluation/Treatment of Thalassemias

• Diagnosis: family clinical tests revealing hyper chromic/ microcytic anemia (peripheral blood smear) + increased HBf with lower Hba and anemia
• Treatment- regular transfusion with chelation therapy to reduce overload,
  • milder requires increased iron absorption= sporadic red cell with chelation/ folic acid
• Alloegenic stem cells are definitive cure (cord family donor) + genetic counselling.
• May need splenectomy is symptoms are worse

Inherited Hemmorrhagic Disease:

• The hemophilias, von wille brand disease etc
• Bleeding disorder with wide clinical serverity depending of deficiency of factor VIII/IX
• (A)/ IX (B) x linked recessive pattern and (B) mutations. A and B= recombinant factor treatment
• Types of Haemophilia. Haem A (classic hemophilia or factor VIII deficiency + mutation) Hem B (Christmas disease for IX-ficiency (less commn)

Clinical Manifestations Hemmophilia-

• Bleeding prolongs over life, with many spontaneous episodes that can kill (delay brain org damage) internal organs/intracranial
• First yr minimal trauma but hematoma forming. Over time= injury from mouth knees elbows. Spontaneous epistaxis with oral bleeding
• During hem arthritis- joint stiffness, pain Evaluat/Management
• Amnio/genetic testing for positive family/bleed hx with PTT test prolomged via factors testing
• Prophylaxis via reguar infusion

von Willebrand disease (factor and platelets bind blood vessels via VII),

• Causes are variable/genetic = deficient brand factor Autosomal recessive, hetero/homozygous
• Congenital and Thrombosis; proteins for clotting are inherited (balance clotting towards homeostasis). Multiple gens role.
• Deficiency in specic proteins with vitamin= arterial thrombosis
• Protein def= heparin for acute events and C conc supplementation required
• S def= purpura in period neonatal
• IiII =heparin, antipatelet and antithrob.
• Anitbody mediated

Primary Immune Thrombocytopenia is the most common thrombocytopenia purpurea in children

• Platelet destruction triggered from drugs, infections (70% virus and EBV/cMV) lymphoma
• Often antiplatelet auto ab is present (plasma membranes-destr)
• Phase assessment after diagnosis required,

Manifest

• Bruisng rash a week after from onset, Petechiae developing to ecchymoses, gums bleed and nosebleed.
• Except signs of bleeding, the child appears well, spleen and bone changes
• Hemorrhages last for 1-2 weeks

Evaluation and Treatment

• Examination reveals very low platelet count
• Ivig to treat (intravenous and Immunoglobulin treatment and cortico suppressers if Thrombocytopenia is severe.
• With/ without treatment- excellent and 75% recover with theee monhs