HEMATOLOGY

Hematologic Markers:Hb: Is the concentration of oxygen carrying protein.

Ht: Is the percentage of whole blood occupied by RBC

MCV: measure average volume/size of RBC. Micro, Normo, Macrocytic

MCHC: measure amount of Hb in the RBC. Normo, Hypo/Hyperchromic

Reticulocytes: Measure circulating immature RBC.

↓ with iron deficiency. ↑ with blood loss

Serum Ferritin: is a storage compound for iron.

As total iron stores are depleted, Serum ferritin levels falls.

↑ levels: Hemolytic anemia, megaloblastic, hemochromatosis

↓ levels: Iron deficiency, Severe protein deficiency

Transferrin: Iron absorbed in small intestine, and transported to plasma

will be bound to a Globulin protein

Total Iron Binding Capacity: Measures transferrin levels:

↑ serum iron concentration. ↓malnutrition, infection

RBC:RBC exist in peripheral blood for 120 days. At the end of RBC life hemolized and extracted from circulation by the spleen.

Normal RBC values vary according to sex and age. If RBC ↓ more than 10%, the patient becomes anemic.

Abnormal findings:

Increased levels Decreased levels

High altitude Hemorrhage (GI bleeding, trauma)

Polycythemia Vera Hemolysis, Drugs

Dehydration Anemias, Dietary deficiency (fe, B-12)

Congenital heart Ds. Leukemia, Overhydration,

Chronic Illness, Kidney failure (Epo)

The Child with Anemia

Minimal level: Up to 18 months- Hb 11g% Ht 33%

Over 18 months- Hb 12g% Ht 35%

Types of Anemia:

The RBC provide information about:

the size or volume (MCV)

weight (MCH)

Hb concentration (MCHC) of the RBC.

RBC distribution width (RDW)

Also order Peripheral Smear: RBC, WBC, Platelets

This microscopic examination can reveal variation in RBC size, shape, color, intracellular content

When checking for anemia:

MCV (mean corpuscular volume or size of a single RBC):

Microcitic - VCM less than 75-80% Fe def anemia, ThalassemiaMacrocitic - VCM above 100% Megaloblastic: B-12/folic acid def.Normocitic - VCM between 75-100%

MCH (mean corpuscular hemoglobin or weight within a RBC):

Microcitic hypochromic: ↓ MCHC/MCV. Iron deficiency, Thalassemia, lead

Macrocitic normochromic: ↑ MCV. No maturation factors (B12,folates, Etho

Normocitic Normochromic:↓ Hb, normal MCHC/MCV. Hemolitic, aplastic anemia Iron def., chronic illness, acute blood loss

Microcytic Normochromic anemia: Renal disease (loss of erythropoietin)

MCHC (mean corpuscular Hb concentration or % of Hb within a RBC):

Hyperchromic: SpherocytosisHypochromic : Fe def. anemia, ThalassemiaNormochromic:

RBC Size (Anisocytosis):

Microcytes (small RBC): Fe def., Hereditary spherocytosis, thalassemia

Macrocytes (larger size): Vit-B12, folic acid def., occasional liver disease

RBC Shape ( poikilocytosis):

Ovalocytes: Megaloblastic anemia

Spherocytosis: (Small and round)- Hereditary Spherocytosis

Elliptocytosis: (Crescent or Sickled shaped)- Sickle cell anemia

Hereditary Elliptocytosis

Leptocytes (Target cells- thin and less hb): Thalassemia

Hemoglobinopathies

Spicule Cell: Uremia, Liver disease, Bleeding ulcer

RBC Color:

Hypochromic (pale): Fe def., Thalassemia, Cardiac disease

Hyperchromasia: Concentrated Hb, usually caused by dehydration

RBC intracellular structures:

Nucleus: RBC maturation process results in loss of nucleus, nucleated RBC (normoblasts) seen

in the peripheral Smear, indicates increased RBC production

Basophilic stippling: lead poisoning

Howell-Jolly bodies: Megaloblastic anemia, Hemolitic anemia,

Heinz Bodies: Hemoglobin Ds, Hemolitic anemia, G6PD

WBC:

Examined for total quantity, differential count and level of maturity

Increased WBC may indicate Leukemia

Decreased may indicate failure of marrow to produce WBC

PLATELETS:

Thrombocytosis: Polycytemia Vera, Leukemia, RA, Chirrosis, Trauma, Tu.

Thrombocytopenia: Bleeding, ITP, Leukemia, DIC, SLE, Ca-Chemo, HA

Drugs: acetoaminophen, H2 agents-Zantac, INH, etc..

Bone Marrow:

Reveals the number, size, shape of RBC, WBC, megakaryocytes, as these cells evolve through several stages of development.

Its microscopic exam reveals estimation of cellularity, determination of presence of fibrotic tissue or neoplasm, estimation of iron storage.

Estimation of cellularity: Is a ratio between Myeloid (WBC) to Erythroid cells (RBC) (M:E ratio). Normal ratio is M3:E1

WBC: ↑: Leukemias , leukemoid drug reaction ↓: leukemia, agranulocytosis, metastatic Tu,, chemo, aplastic

RBC: Hyperplasia: polycythemia Vera, hemolitic anemia, Hypoplasia: Chemo/radiation Tx., iron def., toxic drugs, aplastic

Megakaryocytes: ↑- acute hemorrhage, CML ↓- Radiation/chemo/drugs Tx, aplastic,infiltrative ds.

Lymphocytes: ↑- chronic or viral infections (Mono), CLL, lymphoma

Megaloblastic: Def. of B-12, Folates

Reticulocyte Count:

It is an immature RBC. Determine the bone marrow production of RBC and erythropoietic function.

Increased level Decreased levels

Hemolytic anemia Pernicious anemia

Sickle cell anemia Folic acid def.

Hemorrhage Aplastic anemia

Pregnancy Bone marrow failure

Leukemias Radiation therapy

Chronic infection

Fe def., Depletion of iron stores

WHITE CELL COUNT AND DIFFERENTIALWBC: fight infection and react against foreign bodies.

WBC has 2 components: WBC (leukocytes) and the Differential.

Neutrophils and lymphocytes make up 75-90% of total leukocytes.

Increased of WBC (leukocytocis) infection, inflammation,

leukemic neoplasia.

Also trauma, stress

Decreased of WBC bone marrow failure (after radiation, chemo,

or in agranulocytosis-drug), infections.

NEUTROPHILS (PMN): Produced every 7-14 days, lasts 6 hours. The function is phagocytosis. Acute bacterial infection ↑ neutrophil production ↑ WBC. With neutrophils stimulation, immature forms enter the blood, called BAND cells process called Shift to Left in WBC production ongoing acute bacterial infection

LYMPHOCYTES: Fight chronic bacterial infection and acute viral infection Divided in 2 types: T/B cells. T cells: involved with cellular type immune reaction B cells: involved in humoral immunity (antibody production)

MONOCYTES:

Phagocytic cells that fight bacteria

BASOPHILS / EOSINOPHILS: Are involved in allergic reaction.

Parasitic infestations stimulate the production of those cells

Mild anemias are associated with few or no clinical symptoms or signs; and is detected from a screening measurement of Ht or Hb

Obtain a complete blood count (CBC), reticulocyte count, measurements of the serum iron, total iron-binding capacity (TIBC) and serum ferritin.

Patients with severe anemia and abnormalities in RBC morphology may require a bone-marrow aspirate

If the MCV is suggestive of a megaloblastic anemia, consider testing for RBC and serum folate, serum vitamin B12, and obtain a peripheral blood smear and a bone-marrow evaluation.

NORMAL VALUES

Direct Coombs-DAT (direct antiglobulin test):

Detect autoantibodies against RBC’s, that cause cellular damage leading to hemolitic anemia. Mix the patients RBC’s with Coombs serum. Coombs serum is a solution that contains antibodies against human blood serum. If the patient RBC’s has autoantibodies against RBC’s, the Coombs antibodies will react with the autoantibodies on the RBC’s, causing agglutination of the RBC’s.

Associated disease are: Erythroblastosis fetalis, Lymphomas, Lupus, EBV, , drugs (quinidine)

Indirect Coombs: Detects circulating antibodies against RBC’s. Determines if the patient has serum antibodies (other than the ABO) in the RBC’s that the patient is about to receive by blood transfusion. If it has antibodies, it will cause agglutination. It can be present in a woman Rh- with a fetus who is Rh+

Associated disease: Erythroblastosis fetalis, Acquired hemolytic anemia, Anti-Rh antibodies, Incompatible cross-matched blood.

IRON DEFICIENCY ANEMIA

Results in a ↓ production of Hb, with a small, pale and ↓ # of RBCIron supply is insufficient to maintain normal levels of Hb.

Epidemiology: Common in children from 6 months to 2 years, and teenage boys/girls.Common cause of anemia in developing countries

Pathophysiology:Iron is necessary for oxygen transport by Hb.

Iron is supplied by diet, absorbed in the GI tract (duodenum).

Initially iron stores are depleted but the RBC are normal

When all iron stores decrease, Hb synthesis decrease gradual fall of RBC production in bone

marrow new RBC are smaller and paller decrease tissue oxygenation.

Anemia

• Birth : Mean Hgb = elevated, but highly variable

• 2 mons : “physiologic” anemia 2 SD Hgb = 9.4 g/dL

• 6 mons to 24 mos 2.5 SD Hgb =11.0 g/dL

• American Academy of Pediatrics Hgb < 11.0, Hct < 33% defines anemia

Causes:

-Decrease dietary intake of iron fortified formulas or meat

-Excessive cow’s milk consumption

-Decrease iron absorption

-Blood loss: hemolysis (ABO incompatibility), parasites, cow’s milk enteropathy in infants, GI blood loss

-Decreased production.

-Socioeconomics status

-Duration of breast feeding

-Increased juice, soda pop intake

Clinical Presentation

• Pallor of skin

• Irritability, fatigue, lethargy, tachycardia, tachypnea

• Check anemia on conjunctiva, nail beds.

• Dyspnea, dizziness, SOB, headache hypotension

HX: Family Hx of bleeding disorders dietary history hx of trauma Surgeries

koilonychia : Spooning of the fingernails occurs in children with severe iron deficiency anemia. It refers to abnormally thin nails which have lost their convexity, becoming flat or even concave in shape.

Anemia: Lab Evaluation

• Normal Peripheral Smear • Iron Deficiency Anemia

LAB: CBC = microcytic RBC’s with hypochromia Low Hb / Ht Low MCV (RBC volume) - Microcytosis Low MCH (Hb concentration) for age. Low MCHC - Hypochromic Low ferritin (reflects iron stores depleted) and serum Fe levels (best test) Increased total iron binding capacity (TIBC)

Low Transferrin saturation ( measure iron available for Hb synthesis) Peripheral blood smear: microcytosis, hypochromia, poikilo (shape) / anisocytosis (size)

Low Reticulocytes RDW ↑ (red cell distribution width- Measure red cell size) low Hb, low MCV, and high RDW suggestive iron deficiency

TX: Iron supplement as ferrous sulfate orally for 6 months. 5-6mg/kg/day ferrous sulfate. ↑ Hb 1.0g/dl in 3-4 weeks.

Should be given with orange juice to absorb better the iron.

Should increase in one week after starting oral treatment.

In case of iron toxicity, there is a new alternative to the efficient but painful IV iron chelator deferoxamine.

It is an oral solution called deferasirox, name Exjade, taken once a day.

MEGALOBLASTIC ANEMIA

Etiology: Milk products diet, Folic acid/B-12 deficiency, vegetarians,

drugs that inhibit DNA synthesis (phenytoin) > folic acid.

S/S:

Onset of anemia associated with Pallor, Fatigue, Irritability.

GI symptoms:

Malabsorption/Diarrhea, Vegan diet, Glossitis (red beefy tongue), Atrophy of tongue papilla

Neurological symptoms associated with vit-B12 def:

Difficulty walking, numbness/tingling in hands and feet (paresthesia), ataxia, peripheral neuropathy, positive Babinski sign

Lab: Low Hb < 11g%, Ht, RBC

Increased MCV (macrocitic)

MCH / MCHC normal (normochronic)

RDW elevated

Reticulocytes- decrease.

Peripheral Smear: Oval Macrocytes, hypersegmented neutrophils Increase aniso (size) / poikilocytosis (shape)

Myelogram: Megaloblastic changes (large erythroblasts)

Serum Folates / RBC Folates: low levels. Vit. B-12: low levels

Schilling test: B-12 absorption, measuring urinary excretion

Increase LDH

Tx: Folic Acid- 1-5mg PO daily for 3 B-12 25-100mg IM daily Citrus fruits: Vit-C (transform folic acid in its active form)Diet rich in folates: green vegetables, meat (liver)Reticulocytes ↑ in 2 weeks of therapy. failing to ↑ in 2 months, check Dx.

A smooth, beefy red tongue may be observed in the physical examination of a patient with vitamin B12 deficiency.

APLASTIC ANEMIA: Failure of Bone Marrow to produce: RBC, WBC, Platelets

Etiology: Drugs (chloramphenicol), Toxins, Virus, Radiation.

S/S: Thrombocytopenia: Bruising, Gum/Nose bleed, Petecchia

Anemia: Lethargy, Pallor

Neutropenia: Infection, High fever, Trush, oral ulcerations

Adenopathy / H-Smegaly: Leukemia, Cancer

LAB: Normochromic/Normocytic

Neutropenia < 500 cells

Platelet count < 50.000

Reticulocyte count < 1%

Bone marrow aspirate/biopsy: Hypocellularity.

TX: Bone Marrow transplantation

Immunosupppressive therapy (anti-thymocyte antigen/ Ciclosporine)

Atb

Antifungal oral Tx.

LEAD INTOXICATIONEnvironmental health Ds, leading to a intoxication by heavy metal. Epidemiology: -1,000,000 children aged 6m-5y, have blood lead levels above 30mg/mL -Higher prevalence occurs in Afro-American and Mexican-American children, lower income families, older housing, paint chips, older pipes. Complications:-Seizures -Encephalopathy -Mental retardation, Neuro-developmental impairment

S/S: Hx of peeling paint, behavior changes, abdominal pain, irritability/lethargy, encephalopathy, anemia.

Burton gum lead line: Blue gray discoloration at the gum-tooth, along the lower incisors

LAB: CBC: Microcytic, hypochromic anemia. Basophilic stippling is seen on peripheral smear Blood lead test Free Erythrocyte protoporphyrin: Lead induced Markers Increase serum lead Increase of urine coproporphyrin

Imaging: Abdominal X-Ray: looking for radio-opaque lead ingestion paint chips Long Bones X-Ray: “Lead lines” increased density along transverse lines in the metaphysis of growing long bones

TX: Chelation (EDTA, BAL) Environmental control

Lead Level Screening:

0-9 No immediate concern

10-14 Community/environmental survey

15-19 Retest, educational interventtion

20-24 Monitor periodically, house visit. EDTA provocative test

25-54 Find Pb source EDTA provocative test

55-69 Remove Pb source

70 Emergency Hospitalization.

Tx with BAL + Ca Na EDTA (chelation)

Basophilic stippling on

peripheral smear

SICKLE CELL DISEASE

Sickle cell is an inherited Autosomal recessive blood disorder affecting RBC, where Valine is subtituted for Glutamic acid at codon 6 on the B-globin chain of the Hb, and where in sickle patients, HbS predominates. Normal red blood cells contain hemoglobin A.

These RBC become sickle-shaped (crescent-shaped), having difficulty passing through small blood vessels.

The most common types of sickle cell disease are 3 forms of genotypes: HbSS Ds (sickle cell anemia) ds HbSC Ds (sickle-Hb C Ds) trait HbS-B Sickle Beta Thalassemia.

Incidence: 1:500 ( in the Black population) live births.

Sickle cell trait is inherited from one’s parents, like hair or eye color.

If one parent has sickle cell trait there is a 50% (one in two) chance with each pregnancy of having a child with sickle cell trait.

If both parents have sickle cell trait there is a 25% (one in four) chance with each pregnancy of having a child with sickle cell disease.

When affects one chromossome, the heterozygous condition S.C. Trait

When affects both chromossomes, the homozygous condition S.C. Ds

When one chromossome makes HbS and the other makes no hemoglobin

(B-thalassemia trait) HbS-B.

Sickle cell Ds is a lifelong illness that result in serious health problems.

For this reason, trait awareness is very important.

Hemoglobin A: Is a normal Hb that exist after birth. It is a tetramer with 2 alpha and 2 Beta chain (A2B2)

Hemoglobin A2: Is a minor component of the Hb found in RBC after birth, and consist of 2 alpha and 2 Delta chains (A2d2). Less than 3% of total Hb

Hemoglobin F: Is the predominant Hb during fetal development. The molecule is a tretamer of 2 alpha and 2 Gamma chains (a2g2). Production falls after birth, although some people produces small amounts of HbF during their entire lives.

Hemoglobin S: Is the predominant Hb in people with sickle cell disease. The alpha chain is normal. The disease-producing mutation exists in the beta chain, giving the molecule the structure, a2bS2. People who have one sickle mutant gene and one normal beta gene have sickle cell trait which is benign.

Hemoglobin C: Results from a mutation in the beta globin gene and is the predominant Hb found in people with Hb C disease (a2bC2). Hb C Ds. is relatively benign, producing a mild hemolytic anemia and splenomegaly.

PATHOPHYSIOLOGY:

Genetic abnormality causes the red cells to contain hemoglobin S rather than hemoglobin A, and

through the Beta-valine causes the HbS molecules to be transformed under deoxigenated conditions,

into long fibers that are insoluble and forcing the red cell to become rigid rods and distorted into sickle

or other shapes.

Once the RBCs become distorted,( sickle-shaped), LEADS to:

Microvascular occlusion (endothelial damage to larger vessels, leading to a tickened walls, severe

stenosis, and occlusion), causing tissue ischemia, infarcts, and chronic organ damage.

S/S: Early signs are delayed growth and development, fever, infections Hallmark is Fever

Hand/foot Syndrome- Dactylitis: -Most common age: 6 months to 3 years ( range 3 months – 5 years)-Often the first clinical manifestation-Symmetrical painful swelling of hands/feet. Refuses to bear weight. Fever

Sudden and massive splenic sequestration: (acute blood trapping in spleen resulting in fall in Hb due to sickling). Leading cause of death in children under 5 years.

S/S: spleen enlarged and tender, Hct ↓ by 25%, platelets under 100.000, ↑ in Reticulocytes, pallor, anemia (hemolysis), fatigue fever, jaundice, tachycardia

Due to Splenic dysfunction by intravascular sickling of red cells, this is accentuated by: Hypoxia, Dehydration and Acidosis

Acute Chest Syndrome (Pneumonia):-Seen in more than 50% of Sickle cell patients. -Leading cause of mortality in sickle Cell disease

Sepsis: Younger children: S. pneumoniae Older children: G-/Salmonella

Symptoms : Fever, Cough, Chest/Back pain Tachypnea, ↑ RR, Flaring, Grunting, Hypoxemia Infiltrates in X-ray. Treat with antibiotics

Painful Vaso-Occlusive crises: Pain in large joints, muscle, abd. pain, back pain, knee, shoulder, elbow. PriapismSeen in children after the age of 3-4 yearsSwelling, tenderness, decrease of ROM at site of pain.Pain triggers: stress, infection, menses, trauma, change of weather.

Aplastic Crisis: Decrease of RBC production due to decrease of Hb/Retic Count. Parvovirus B-19 (mc) Anemia (hemolysis), Fatigue, pallor, decrease retic.

Other Ds: Meningitis, Osteomyelitis (Salmonella), Sepsis (mcc-death)

LAB:

Hemoglobin Electrophoresis is definitive diagnosis:Absence of hemoglobin A Presence of hemoglobin S with mild elevation of hemoglobin FSickle cell anemia: Hgb-S 85-98% Hgb-F 2-20% Hgb A2 0-2%

Sickle Cell trait has Hgb-S of 40% and Hgb-A of 60%

CBC: low Hb (6-10gm/dL)/Ht presence of sickle cells/ Howell-Jolly Bodies on peripheral smearIncrease WBC, PlateletsReticulocytes: elevated (5-15%)

X-Ray: evidence of osteolysis, periostitis, bone reabsoption.

Bone Scan: differentiate bone infarction from osteomyelitis

Chemistry: LDH-↑, AST- ↑ Unconjugated bilirubin- ↑

TX:

*Hydroxyurea- decrease number and severity of pain crises.

*Pain: NSAID’S or narcotics (Demerol or Morphine Sulfate)

*VOC ( vaso occlusive crisis)- fluids (Hydration), Oxygen, warmth.

*Blood transfusion (packed RBC) during aplastic or sequestration crises (fall in hb)

*Ceftriaxone, Cefuroxime: S. Pneumonia, H. influenza

*Erythromycin: Mycoplasma Pneumonia

*PCN prophylaxis: after 3 months: oral PCN 125mg BIDqd up to 2 years after 2 years: 250mg BID until 5-6 years*Pneumoccocal vaccine (after 2y), influenza virus vaccine, Hib/ Hep-B vaccine specially in patients with splenectomy

*Bone marrow transplantation.

*Genetic counseling

Peripheral blood smear of a child with hemoglobin SC disease. Sickle cells are seen less frequently in this disease, whereas target cells are more prominent.

Thalassemia

Are hereditary anemias as a result of mutations affecting the synthesis of hemoglobin. Normal Hb is a tetramer of 2 alpha and 2 beta chains.

-Alpha Thalassemia: decrease or total lack of alpha globin sysnthesis

-Beta Thalassemia: Decrease or lack of beta globin sysnthesis.

Pathophisiology: Several mutations in alpha and beta globin genes lead to various different phenotypes of alpha/beta Thalassemia, leading to varying levels of anemia depending on the gene defect

Clinical Classification:

Silent carrier (alpha/Beta): hematologically normal

Thalassemia trait (alpha/beta): mild anemia w/ microcytosis, hypochromia

Alpha Thalassemia Ds: severe hemolytic anemia, jaundice, splenomegaly

B-Thalassemia Ds major(Cooley anemia): severe anemia, H/Smegaly, growth↓

Epidemiology: Alpha Thalassemia: Asian, African, Afro-American people

Beta Thalassemia: Mediterranean countries, Mideast, India, Pakistan

S/S: Onset in first year of life May present with signs of CHF due to severe anemia Pallor, Hepatosplenomegaly, Jaundice Chipmunk facies in Beta thalassemia due to facial bone expansion by hyperthrophic marrow Growth retardation with FTT

Prognosis:

Life expectancy improved with regular transfusions and chelation therapy. Also a Bone Marrow transplant from a histocompatible sibling donor gives long term survival

LAB: CBC for anemia with low MCV, MCH, MCHC (↓ in ά/β) Hb 9-10 g/dl –Thalassemia trait Hb 6-7g/dl - in alpha Thalassemia Hb less than 5 g/dl in thalassemia major

Presence of Basophilic stiplings

Peripheral Smear: Mycrocitosis, hypochromia Mild aniso/poikilocytosis in Thalassemia Trait Severe aniso/poikilocytosis in alpha and major (beta) Target cells, Teardrop cells, Polychromasia

Reticulocytes: elevated in Thalassemia syndromesIndirect Bilirubin: Increased in severe ThalassemiaSerum ferritin elevated in transfused Beta Thalassemia

Hemoglobin Electrophoresis:

Alpha Thalassemia Trait: 2 defective genes. 90% HbA

Alpha Thalassemia Ds: 3 defective genes. 5-30% alpha thalassemia, remainder HbA

Beta Thalassemia Trait: HbF 1%-5%, HbA2 3.5-8%, remainder HbA

Beta Thalassemia Major: HbF 20-100%, HbA2 2-7%, HbA 0-80%. In most cases, HbA is not detected.

TX:

Silent carriers alpha/beta: genetic counseling only

Alpha disease: Folic acid Transfusions when necessary Splenectomy if evidence of hypersplenism

Beta Thalassemia major:

Transfusions of RBC every 3-4 weeks to maintain Hb at 9-10 g/dl

Serum Ferritin, TIBC, Transferrin saturation, LFT: test every 3 months.

Chelation therapy with Desferroxamine , avoiding iron overload

Splenectomy if transfusion require more than 200 ml/kg/year

Folic acid daily

Penicillin prophylaxis to all splenectomised patients

Pneumococcal/HIB vaccine prior to splenectomy

Bone Marrow transplantation using sibling donor

Thalassemia major. A- This peripheral blood smear in a child with thalassemia major shows a hypochromic, microcytic anemia with prominent nucleated red blood cells surrounding the PMN cells and lymphocytes. B- Labeled schematic of peripheral blood smear.

A- Maxillary hyperplasia resulting from an increased marrow space in a child with thalassemia major.

B- Skull R-X of the same patient demonstrates an increased marrow cavity of the skull and facial bones.

Idiopathic Thrombocytopenic Purpura (ITP)Thrombocytopenia 2ary to ↑ destruction of platelets by circulating anti-platelets antibody. ITP is the most common acquired platelet disorder

Classified as : Acute- remission in less than 6 months

Chronic- remission more than 6 months

Etiology: Viral illness ( varicella, mumps, rubella, Mono) 65%

Epidemiology: Incidence 4-8/100.000 under 15 years. Males=females

Peak age: 2-5 years. Younger than 1 year or over 10 years are

more likely to develop chronic ITP

Pathophysiology: Immune mechanism- autoantibodies to foreign antigen

SIGNS: Most cases is preceded by a viral infection 1-3 weeks before onset. Onset is acute in children, with overnight develop/ of petecchia, purpura.Presence of unusual bruises, urine/stool blood, epistaxis, gum bleeding Recent immunizations (MMR).Drug history affecting platelets: ASA, heparin, seizure meds.

S/S:

Clusters of petecchia, or large bruises on skin

Purpura in the oropharinx, dry blood or clots in the nares

Fundoscopic exam is important

LAB:

CBC: Normal WBC/Hb with Thrombocytopenia

PT/PTT: Normal

Bleeding Time: prolonged

Peripheral Smear: Normal, except Thrombocytopenia

Bone Marrow: Normal or increased megakaryocytes.

only if treating with Steroids and exclude leukemia

TX: - IV Corticoids. Then oral steroids 2 mg/d for 2-4 weeks

- IV Immunoglobulin (IVIG): 1g/kg/d

HEMOPHILIAInherited bleeding disorder caused by the absence or severe deficiency functioning of plasma coagulation factor VIII or IX.

Hemophilia A: deficiency of factor VIII

Hemophilia B (Christmas disease): deficiency of factor IX

Epidemiology:

Distribution: Hemophilia A: 80-85%

Hemophilia B: 15-20%

Incidence: Hemophilia A: 1/5000 male births

Hemophilia B: 1/25,000 male births

Hemophilia A defective gene is carried on the X chromossome

Inherited as sex-linked recessive disorder; males are affected, females are carriers

Rarely, a girl is born with hemophilia. It happen if her father has hemophilia and her mother is a carrier.

Males born to a woman that is a carrier, has 50% risk of having the Ds.

Some males with the disorder are born to mothers who aren’t carriers. In these cases, a mutation occurs in the gene as it is passed to the child.

Pathophysiology:Thrombin generation delayed in patients with absent/reduced factor VIII/IX

There is delayed formation of a fibrin clot, and severity of the disorder, is determined by the level of clotting factor def.:

Mild hemophilia 5–30 percent of normal factor Moderate hemophilia 1–5 percent of normal factor Severe hemophilia Less than 1 percent of normal factor

S/S:

Neonatal period: Bleeding from circumcision site

Hematoma after injections

Infancy and Childhood:

Bleeding spontaneously after trauma, GI, teeth eruption, epistaxis

Deep soft tissue bleeding , easy bruising

Hemarthrosis (knees, elbow, ankles) occuring after a trauma

Joint examination:

Acute Hemarthrosis: motion limitation of the joint,

warmth, swelling, tenderness, decrease ROM, proximal muscle weakness

LAB:

Hemophilia A:

Factor VIII- Decreased

Platelet count-Normal

Bleeding Time, Prothrombin Time, Fibrinogen: Normal

(A)PTT (activated partial thromboplastin Time): Prolonged

2-3 times normal

Hemophilia B:

Factor IX- Decreased

(A)PTT- Prolonged

Platelet Count, Bleeding Time, Fibrinogen- Normal

TX: Hemophilia A:

-Factor VIII replacement products:

*Recombinant non- plasma derived viral inactivated factor VIII concentrate

*Monoclonal purified plasma derived viral inactivated factor VIII concentrate

*Cryoprecipitate. Risk of Hep. B, C, D. Use in extreme cases

-DDAVP (Desmopressin acetate): stimulates release of endogenous factor VIII

Only for mild or moderate factor VIII deficiency. IV or intranasal spray

-Antifibrinolytic Therapy:

For oral mucosa bleeding, dental extractions

*Epsilon aminocaproic acid 50 -100 mg/kg dose PO q6 or Tranexamic acid

Adjuvant therapy for hemarthrosis: Immobilization, RICE, splints, casts

Inheritance Pattern for Hemophilia—Example 1

The diagram shows one example of how the hemophilia gene is inherited. In this example, the father doesn't have hemophillia (that is, he has two normal chromosomes—X and Y). The mother is a carrier of hemophilia (that is, she has one abnormal X chromosome and one normal X chromosome). Each daughter has a 50 percent chance of inheriting the abnormal gene from her mother and being a carrier. Each son has a 50 percent chance of inheriting the abnormal gene from his mother and having hemophilia.

Inheritance Pattern for Hemophilia—Example 2

The diagram shows one example of how the hemophilia gene is inherited. In this example, the father has hemophilia (that is, his X chromosome is abnormal). The mother isn’t a carrier of hemophilia (that is, she has two normal X chromosomes). Each daughter will inherit the abnormal gene from her father and be a carrier. None of the sons will inherit the abnormal gene from their father, and, therefore, none will have hemophilia.

TX:

Hemophilia B:

Factor IX concentrate infusion that also contains factors II,VII,X

Viral inactivated factor IX concentrate

Prophylaxis:

Avoid trauma in sports, good dental hygiene, Immunizations Never give Aspirin, Nsaid’s- Interferes with platelet function

VON WILLEBRAND DISEASEAutosomal dominant disorder resulting from a defective Von Willebrand Factor, causing ineffective platelet adhesion.

Decrease in vWF, will reduced Factor VIII-R

Epidemiology:

Affects Males/females same proportion. Occurs in 1/500 births

Genetics:

Type I: Follow a dominant inheritance pattern

Type II: Heterozygous patients have been described

Type III: Follow a recessive inheritance pattern

S/S:

Mucocutaneous bleeding, epistaxis, gum bleeding, menorrhagia, bruises

In severe vWF, manifestations as Hemophilia A (hemarthrosis)- Type III

Type I/II has mild symptoms, often are undetected

LAB: Bleeding Time: Prolonged vWF/VIII factor: DecreasedPT, Platelet count: Normal aPTT: Mildly/moderately ProlongedRistocetin cofactor activity: Decreased (!!!) induced vWF bind to platelets

TX: Avoid heavy contact sports / Aspirin

Type-I: DDAVP (Desmopressin acetate) IV/Intranasal. Release factor VIII Humate-P: viral attenuated vWF containing Factor VIII concentrate Avoid Cryoprecipitate- is not virally attenuated (inactivated) HIV/Hep-B infection risk

Aminocaproic Acid: For oral cavity bleeding Hepatitis B vaccine given prior to exposure to plasma derived product

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)Malignant disorder of lymphoblasts occurring in Bone Marrow as a result of clonal proliferation of a single lymphoblast that undergone malignant change

Etiology:-Unknown

-Exposure to ionizing radiation-Chemicals

-Viral infections: HTLV I associated with adult T cell leukemia

HTLV II associated with hairy cell leukemia

-Immunodeficiencies

-May be classified as B or T cell

Epidemiology:

-Most common Cancer of childhood. 75% is ALL

-Incidence: peak incidence: 2-5 years old.

Common in whites/boys.

S/S:

Are due to infiltration of leukemic cells into normal tissues resulting in:

-Bone Marrow failure (anemia, neutropenia, thrombocytopenia)

-Specific tissue infiltration (lymph nodes, liver, spleen, brain, bone, gonads-testicular enlargement) Fever, Petecchia, weight loss, irritability, fatigue, pallor, bruising

Bone pain, limp, tenderness, arthralgia - 90% long bones

Lymph nodes enlargement, hepatosplenomegaly

CNS involvement: Headache, vomiting, seizures, papilledema

Sternal tenderness (bone marrow infiltration)

Thrombocytopenia: Petecchia, ecchymosis, subconj/retina hemorrhage

LAB:

CBC: WBC-Vary from 5000-100,000 average < 10,000 in 50% of cases 10,000-50,000 in 35% of cases Anemia: Hb < 7.5g/dL in 60% Neutropenia: < 500/mm3 Thrombocytopenia: < 100,000/mm3 in 75 % of cases < 20,000- 20% 20,000/100,000 - 55%

Bone Marrow aspirate: > 25% leukemic lymphoblasts is diagnostic

CFS fluid: Check for lymphoblats and increased PROTEIN, decreased GLUCOSE.

X-Ray: Chest- check for anterior mediastinal mass Long Bones-multiple punctate osteolytic lesions

Others: Coagulation panel: PT, PTT, fibrinogen Liver, renal and fluids panel, LDH

Presence of Philadelphia chromossome is a bad prognostic sign

Sudan Black stain- Negative

TX:

Is according to risk groups: 4 phases of Therapy

Induction: To achieve remission (< 5% of blasts in BM).

Usually 3-4 drugs: Vincristine, Prednisone, L-asparaginase

w/wo Doxorubicin, Intratecal metotrexate.

Consolidation and CNS prophylaxis: To prevent CNS disease.

Intrathecal metotrexate w/ oral 6-mercaptopurine (6MP)/MTX-standard risk

Intrathecal metotrexate w/ cranial radiation, oral 6MP/MTX-High risk pt.

Delayed intensification: To further decrease leukemic burden.

Vincristine, Metotrexate, L-Asparaginase, Doxorubicin, Cyclophosphamide

Cytosine Arabinoside (ARA-C), 6-Thioguanine (6-TG), Intrathecal MTX

Maintenance:-Daily oral 6MP-Weekly MTX and monthly pulses of Vincristine and prednisone-Intrathecal metotrexate for 2,5-3 years

CNS Leukemia at diagnosis:

-Cranial Radiation

-Triple intrathecal (MXT, ARA-C, Hydrocortisone) in addition to Tx

Bone Marrow transplant to be considered for relapsed patients.

Supportive Care:

Hydration, Avoid vigorous exercices

Alkalization with NaHCO3 to keep urine pH 6.5

Blood/Platelet transfusions

Broad spectrum ATB for fever and infections.

Atb for Pneumocystis

No live vaccine during treatment, Avoid vigorous exercises

Prognosis:70% with ALL achieve long term survival Risk factors for poor prognosis = age < 1 year or >10 years, WBC >100,000, CNS disease, Mediastinal mass

Swelling of the cervical lymph nodes

Disseminated Petecchya

Triad: Pallor-cutaneous hemorrhages- swelling

of lymph nodes in a 3 year old girl

Five days later: extensive cranial hemorrhage, and oral mucosa. Mickulicz syndrome: swelling on infiltration of the lacrimal, salivary and parotid gland

Bone Marrow aspirate in

ALL child

ACUTE MYELOID LEUKEMIAIs a clonal proliferation of malignant myeloblasts.

Etiology:

-Exposure to ionizing radiation

-Exposure to Benzene

-Exposure to alkylating agents:-Cyclophosphamide

-Chlorambucil

-Nitrogen mustard

Exposure to Epipodophyllotoxins: -VP 126/-VM 26

Epidemiology: 15-20% of childhood acute leukemia is AML Ratio AML to ALL= 1:4. Boys/girls affected equally Leukemia in first 6 weeks of life is AML Worse prognosis than ALL

S/S: Fever, Pallor, fatigue, weakness, bleeding, bruising, recurrent Inf.

Bone pain (less than ALL), CNS Sx rare.

Bone tenderness, purpura

Hepato/Splenomegaly, Gengival hypertrophy, Petechia, ↑ lymph

LAB:

CBC: Normocytic normochromic anemia

WBC > 10,000 Neutrophils, Platelets, Monocytes: Decreased

Peripheral Smear: Myeloblasts are seen.

AUER rods pathognomonic for AML

Bone marrow Aspirate: Hypercellular with 30% myeloblasts,

Cytochemistry: Blasts are positive for myeloperoxidase/ Sudan black

PT, PTT: Increased.

Fibrinogen: Decreased (DIC)

CSF cytology: > 5 WBC/mm3 CNS Ds.

X-RAY: Bone destruction and periosteal elevation

TX: Most effective drugs for remission in AML:

Induction:

Anthracyclines: Doxorubicin, Daunomycin

Cytosine-Arabinoside (ARA-C) with or without 6-thioguanine (6TG)

Dexamethasone. All drugs produces transient bone marrow aplasia.

Consolidation: therapy usually with: ARA-C and L-Aspariginase

Intrathecal ARA-C for CNS prophylaxis

Maintenance: with VP16, ARA-C, 6TG, Daunomycin, Dexamethasone.

Duration of therapy is usually 6-9 months.

Allogeneic Bone Marrow transplant is best Tx for AML in remission.

Supportive care:

Hydration, alkalization of urine, and Allopurinol during induction.

Broad spectrum ATB (Pneumocystis) Nystatin/Fluconazole -Fungal

HODGKIN LYMPHOMAMalignant enlargement of lymph nodes characterized by a cellular infiltrate with multinucleated giant cells (REED-STERNBERG cells)

Epidemiology:

Bimodal age distribution: Early, between 15 / 30 years and after 50 years

Childhood cases: rare before 8 years old

There is a 3:1 male predominance in childhood Hodgkin disease.

Etiology: Familial clustering, suggests the role of both genetic and

environmental (radiation, infection) factors

Pathophysiology: Exact cause is unknown.

Reed-Sternberg cells are the malignant cells of Hodgkin lymphoma. They may originate from a activated B/T lymphocytes or from antigen-presenting cell.

Rye Classification: Lymphocyte predominant- Mixed cellularity,

Lymphocyte depleted- Nodular sclerosis.

S/S:

Fatigue, anorexia, weight loss, unexplained fever, night sweats

Painless, firm lymphadenopathy (confined to 1or 2 nodes areas, Supraclavicular and Cervical nodes)

Mediastinal lymphadenopathy causes cough or difficulty to breath.

Hepatosplenomegaly and bone tenderness in advanced stages.

LAB:

CBC: Leukocytosis, eosinophilia

ESR / Serum copper level: Elevated

Cellular immunity (cutaneous antigen testing): Anergy

Patient is predispose to infections: protozoal (Pcp, toxo), fungal, viral (V.Z

Baseline Thyroid function (pre-radiotherapy)

Echo, PFT, Liver (LDH), Renal Function tests

Definitive diagnosis is BIOPSY of lymphnodes

Imaging:

Chest X-ray (PA/Lateral) look for mediastinal mass. !!! for staging

CT scan (chest, abdomen, pelvis) R/O metastasis. !!! for staging

CT or MRI of Spine Symptoms of cord compression suspected.

Special Tests:

Bone Marrow Biopsy

Gallium Scan: Detects residual disease in mediastinum

Bone scan: Evaluates Bone involvement (Optional)

ANN ARBOR STAGING CLASSIFICATION:

I- Involvement of a single lymph node region

II- Two or more lymph node regions on the same diaphragm side

III- Lymph node regions on diaphragm both sides with spleen involve/

IV- Diffuse or disseminated involvement of one or more extra-lymphatic organs or tissues with

or without associated lymph node involvement

TX:

Radiotherapy: Dosis administered in fractions 5 times/week

Chemotherapy: Multiple agents allow different mechanism of action.

Follow-Up: Monthly CBC

CT scan every 3 months for 2 years, then every 6 months for 3 Ys.

Prognosis: With Chemo and Radiotherapy, a five year survival ranges from:

88-100% in low stage disease

54-94% in advance stage disease

NON HODGKIN LYMPHOMA

Is a malignant proliferation of cells of lymphocytic or histiocytic lineage

Burkit Tumor- Monoclonal tumor of lymphoblasts type B

Epidemiology:

Incidence of 1-1,5/100,000 children

Peak age: 7-11 years, Ratio of 3:1 M/F , Genetic predisposition

Environmental factor: Drugs (immunosuppressive), Radiation, Virus (EBV )

Pathophysiology:

NHL can be divided in 3 categories:

*Small noncleaved-cell lymphoma: 40% of childhood NHL. Variety of B- cell markers are present

*Lymphoblastic lymphoma: 40% of childhood NHL. Predominantly of thymocyte (T-cell origin)

*Large-cell lymphoma: 20% of childhood NHL. They are of B-cell origin.

S/S:

1)B-cell lymphomas: Abdomen, head, neck

Fever, weight loss, anorexia, fatigue, Lump in neck, abdominal mass with pain, swelling, nausea or vomiting, and change in bowel habits.

Small non-cleaved cell lymphoma: Abdominal mass- ileocecal region, appendix ascending colon. Intussusception in children over 6 years, GI bleeding. Affects also testis, parotid gland.

2)T-cell lymphomas: Mediastinum

Mediastinal tumor symptoms: cough, hoarseness, dyspnea, orthopnea, chest pain, headache, blurred vision, syncope

Painless ↑ of the cervical, supraclavicular, and axillary nodes are associated with an anterior mediastinal tumor.

Lymphoblastic lymphoma: Mediastinal mass with pleural effusions and lung infection with or without SVC (swelling, plethora, cyanosis of face and neck, diaphoresis, stridor and wheezing).

LAB: CBC, Liver and Renal function studies

Bone marrow aspiration and biopsy (GS)

Lumbar puncture with CSF cytology

Cytogenetics and immunophenotyping of tumor

Tissue Biopsy for definitive diagnosis and staging

St. Jude Children’s Research Hospital Staging System

Stage I- One Tu. (extranodal) or single nodal area, excluding mediastinum or abd

Stage II- Single tumor with regional nodal involvement, two or more tumors or nodal

areas on one side of the diaphragm, or a primary

GI tu. with or without regional node involvement.

Stage III- Tumors or lymph node areas on both sides of diaphragm, or any primary

paraspinal or epidural tumors

Stage IV- Bone marrow or CNS diseases regardless of other sites

Imaging: Chest X-ray PA/Lateral Bone Scan Abd. U/S CT abdomen, Chest and pelvis MRI

TX: Depends on the staging of the tumor Radiotherapy, chemotherapy, surgery, bone marrow transplant

Prognosis: Depends on Tumor infiltration/treatment initialized at diagnosis.

Burkitt

Lymphoma