HEMATOLOGY CONFERENCE Cruz, Kristen, Cruz, Riza, Cudal, Beinjerinck Ivan, Dancel, Jonathan Carlo, Dans, Kunny, Daquilanea, Michee Grace

General Data S.G 4year old Female Birthday: Novaliches Q.C Informant: Mother Reliability: Fair

Chief Complaint PALLOR

HISTORY OF PRESENT ILLNESS - Noted Pallor on her face and hands - consulted: CBC: low hemoglobin - observed - THM: Multivitamins + iron (.5mL QD) 4 years PTA: (October 2005) - FF. up repeat CBC: Hemoglobin still low - requested Iron study but not done - considered: β-Thalassemia - given Folic Acid November 2005

- sought consult - advised for blood transfusion - Type O+ December Iron studies: ↑iron - Diagnosed as β-Thalassemia August 2006 HISTORY OF PRESENT ILLNESS

Multiple transfusion 2-3 months Desferoxamine INTERIM For Blood transfusion HISTORY OF PRESENT ILLNESS ADMISSION

Review of systems No weight loss No pruritus, cyanosis no easy fatigability No abdominal pain, no constipation No dysuria, oliguria No loss of consciousness, seizures, alteration in mental status

Maternal History Gestational History Born to a 35 year old G4-P3, (+) prenatal check-up since 1 st month AOG Hepatitis and gestational diabetes screening was not done denies of any exposure to infections and roentgen studies. Vitamins: Ferrous Sulfate, Multivitamins UTZ: (7 th, 9 th month)

Neonatal History Birth – Patient was born term – AGA unrecalled, BW 4 lbs – unrecalled APGAR but claimed to be generally stable. – No Newborn screening

Feeding History Feeding - Birth- 1 year: exclusively breast feeding - 8 months: complementary feeding - 1year : chocolate drink - eats everything except vegetables

Personal History Past Illnesses Sept – Dengue Fever, PICU No history of trauma nor prior injuries. No history of prior surgeries.

Personal History Immunizations – BCG – Hepa B – DTP – OPV – Measles – Hib – MMR – Varicella – Typhoid

Growth and Development Developmental milestones Social smile – more than 4 months Head control – more than 4 month old Sits alone – more than 5 months Roll over – 4 months Walks alone – 1 year Runs – 2 years Feeds self with crackers – 6 months First words – 11 months Toilet train: 3 years Scribbles: 2 years Present assessment:

Family Profile AgeEducational Attainment OccupationHealth Status Father42High schoolLaborerApparently healthy Mother39Vendor/house wife Apparently healthy Nel Patrick182 nd year college Apparently healthy Mark Darwin11Grade 5Apparently healthy Tracy9DeceasedApparently healthy

Family History (+) Hypertension (+) Cardiac disease – grandmother (+) Asthma – father side β- Thalassemia – sister (-) bleeding disorders (-) PTB (-) Diabetes mellitus (-) Kidney Disease

Socio-economic Profile The patient lives in a bungalow, owned, made of wood with her parents and siblings. The father is the breadwinner while the mother is the primary caregiver. Water source for drinking is NAWASA They don’t have any pets but there are stray dogs, chicken and a piggery in their neighborhood. The garbage is collected twice a week and they practice waste segregation.

Physical examination Awake, alert, ambulatory, no signs of dehydration, not in cardiorespiratory distress, well-nourished, well- developed BP 90/50 HR100 bpm, reg RR24 cpm T36.3C, wt 14.7kg (z=-1), ht 94.5cm (Z=below -2) Warm moist skin, pale, no jaundice, no cyanosis, no rashes Atraumatic head, normocephalic, frontal bossing Pale palpebral conjunctivae, anicteric sclera, pupils 2- 3mm ERTL

Nasal septum midline, no nasal congestion, no tragal tenderness, (-) aural discharge Moist buccal mucosa, midline uvula, nonhyperemic posterior pharyngeal wall, tonsils not enlarged Supple neck, thyroid not enlarged, (+)cervical lymphadenopathy Symmetrical chest expansion, no retractions, clear breath sounds Physical examination

Adynamic precordium, no murmurs Globular abdomen, NABS, soft, nontender, no palpable masses, liver span 12cm, (+)splenomegaly Straight spine, no deformities No edema, no cyanosis, no clubbing Pulses full and equal on all extremities, pale nail beds Physical examination

Neurologic Examination Cerebrum: Awake, alert, GCS 15 Cranial nerves: I – XII intact Motor: 5/5 on all extremities, No tremors, atrophy, fasciculations Reflexes: DTR’s 2+, (-) Babinski Meningeal signs: No nuchal rigidity

PRESENTING MANIFESTATIONS Low hemoglobin Low hematocrit (+)splenomegaly Pallor (+) family history

Approach to Diagnosis Signs and Symptoms or Laboratory findings pathognomonic of a disease Signs and Symptoms or Laboratory findings pointing to an organ or part of an organ system Signs and Symptoms or Laboratory findings pointing to an organ or part of an organ system Signs and Symptoms or Laboratory findings pointing to a group of diseases Signs and Symptoms or Laboratory findings whose mechanism is well understood Signs and Symptoms or Laboratory findings found in the least number of disease

Harrison’s Principle of Internal Medicine 17 th edition

MCV ANEMIA Low Iron Deficiency, Thalassemia, Lead Poisoning, Chronic disease Normal Reticulocyt e count High Folate deficiency, Vit B12 def, Aplastic anemia, Preleukemia, Immune hemolytic anemia, Liver dse

b-Thalassemia minor (heterozygous mild hypochromic anemia normal serum iron increased red cell number Ratio of mean red cell volume (MCV) to red cell count is <13 Increased HgA2 b-Thalassemia major (homozygous) severe hypochromic anemia with microcytosis anisocytosis, and poikilocytosis by 12 months. Mild ↑serum indirect bilirubin Hb electrophoresis shows only Hb F and A2

COURSE IN THE WARDS On admission CBC requested Pre-BT medications: – Paracetamol 250mg/5ml (3ml) – Diphenhydramine 12.5mg/5ml (10ml) Transfused with properly typed and crossmatched 1’u’ pRBC divided into 2 satellite bags 2 nd HD Applied to SAGIP Given Deferroxamine 500mg/vial OD x 5 days – Reconstitute 1 vial of Desferroxamine with 2 ml sterile water. Once dissolved add 8ml PNSS to make 10mL solution then give per subcutaneous infusion over 12 hours

3 rd and 4 th HD Patient was stable 5 th HD COURSE IN THE WARDS

Laboratory Results 11/24/09 Reference value White Blood Cell7.73 x 10^9/L4 -12 Red Blood Cell3.00 x 10^12/L4 – 5.30 Hemoglobin64 g/L115 – 145 Hematocrit – 0.43 MCV66.00 fL79.40 – Mean Corpuscular Hb21.30 pg25.60 – Mean Corpuscular Hb Conc.32.3 %32.20 – RBC Distribution Width21.30 %11.60 – PlateletAdequate Neutrophils – 0.55 Lymphocytes – 0.46 Monocyte – 0.08 Eosinophil – 0.06

11/23/09Reference value Creatinine23.29 umol/L26.55 – SGPT/ALT U/L Ferritin> 2000 ug/L Laboratory Results

TREATMENT Before chronic transfusions are initiated, the diagnosis of β 0 - thalassemia should be confirmed and the parents counseled about this lifelong therapy. Initiating transfusion and chelation therapy can be difficult for parents to face early in their child's life. Before transfusion therapy is begun, a red cell phenotype is obtained; blood products that are leukoreduced and phenotypically matched for the Rh and Kell antigens are required for transfusion. If there is the possibility of a bone marrow transplant, the blood should be negative for cytomegalovirus and irradiated.

Transfusion therapy promotes general health and well-being and avoids the consequences of ineffective erythropoiesis. A transfusion program generally requires monthly transfusions, with the pretransfusion hemoglobin level >9.5 and <10.5 g/dL. In patients with cardiac disease, higher pretransfusion hemoglobin levels may be beneficial. Some blood centers have donor programs that pair donors and recipients, decreasing the exposure to multiple red cell antigens. TREATMENT

Transfusional hemosiderosis causes many of the complications of thalassemia major. – Transfusional hemosiderosis can be prevented by the use of deferoxamine (Desferal). Accurate assessment of excessive iron stores is essential to optimal therapy. – The serum ferritin level is useful in assessing iron balance trends, but does not accurately predict quantitative iron stores. – Undertreatment or overtreatment of presumed excessive iron stores can occur when a patient is managed based on the serum ferritin level alone. Measurement of the iron level by liver biopsy is the standard method for accurately determining the iron store. – Although quantitative liver iron measurement accurately guides the use of iron chelators, it may not reflect cumulative changes in cardiac iron. TREATMENT

A ferritometer and specialized MRI software are emerging alternatives for liver biopsies. Patients can have cardiac iron overload at the time of a safe liver iron measurement. Many thalassemia centers monitor cardiac iron with T2 weighted MRI imaging, but routine application of this technology has not been implemented across all sites. TREATMENT

Deferoxamine chelates iron and some other divalent cations, allowing their excretion in urine and stool. – Deferoxamine is given subcutaneously over 10–12 hr, 5–6 days a week. – Side effects include ototoxicity with high-frequency hearing loss, retinal changes, and bone dysplasia with truncal shortening. – The number of hours deferoxamine is used daily is more important than the daily dose. – High-dose, short-term infusions increase toxicity with little efficacy. P – lasma non-transferrin-bound iron (NTBI) is most likely responsible for the serious iron injury. When deferoxamine is infusing, it binds NTBI. – The 24 hr deferoxamine infusion has been shown to reverse cardiomyopathy in patients with excessive iron stores in the heart that result in symptomatic congestive heart failure. TREATMENT

Deferiprone is a new iron chelator approved by the U.S. Food and Drug Administration for children >2 yr of age (see Chapter ). – Deferiprone may not be as effective as deferoxamine in total body iron chelation, but may be more effective in removing cardiac iron. – Side effects include neutropenia, and weekly blood counts are needed. Other iron chelators are being studied for oral and subcutaneous use. ICL670 is an oral chelator that appears effective in phase III trials and may be approved for use in the U.S. in the near future. Bone marrow transplantation has cured >1,000 patients who have thalassemia major. – Most success has been in children younger than 15 yr of age without excessive iron stores and hepatomegaly who have HLA-matched siblings. – All children who have an HLA-matched sibling should be offered the option of bone marrow transplantation. TREATMENT

DISCUSSION

Thalassemias -genetic disorders in globin chain production -β-thalassemia- either a complete absence of β-globin gene production (β 0 -thalassemia) or a partial reduction (β + -thalassemia) - α-thalassemia - α-globin gene production is either absent or partially reduced

EPIDEMIOLOGY Approximately 20 common alleles constitute 80% of the known thalassemias worldwide 3% of the world's population carries genes for β-thalassemia Southeast Asia, 5–10% of the population carries genes for α-thalassemia

THALASSEMIA autosomal recessive blood disease. the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin. Reduced synthesis of one of the globin chains can cause the formation of abnormal hemoglobin molecules, thus causing anemia,

Overview Hemoglobin – oxygen-carrying component of the red blood cells – consists of two different proteins alpha beta. If the body doesn't produce enough of either alpha or beta proteins the red blood cells do not form properly and cannot carry sufficient oxygen.ANEMIA

Alpha Thalassemia Four genes (two from each parent) are needed to make enough alpha globin protein chains. commonly found in Africa, the Middle East, India, Southeast Asia, southern China, and occasionally the Mediterranean region. types – Silent Carrier State. – Alpha Thalassemia Trait or Mild Alpha Thalassemia. – Hemoglobin H Disease. – Hemoglobin H-Constant Spring. – Hydrops Fetalis or Alpha Thalassemia Major Cooley's Anemia Foundation, Inc.

PATHOGENESIS OF Alpha THALASSEMIA relatively fewer α-globin an excess of β- and γ-globin chains. These excess chains form – Bart's hemoglobin (γ 4 ) in fetal life – Hb H (β 4 ) after birth. Prenatally, a fetus with α-thalassemia may become symptomatic because Hb F requires sufficient α-globin gene production, whereas postnatally, infants with β-thalassemia become symptomatic because Hb A requires adequate production of β-globin genes.

Inheritance Pattern for Alpha Thalassemia

Beta Thalassemias People whose hemoglobin does not produce enough beta protein It is found in people of Mediterranean descent, such as Italians and Greeks, Arabian Peninsula, Iran, Africa, Southeast Asia and southern China.

Pathogenesis of Beta Thalassemia Inadequate β-globin gene production – leading to decreased levels of normal hemoglobin (Hb A) imbalance in α- and β-globin chain production. excess of α-globin chains relative to β- and γ- globin chains; α-globin tetramers (α4) are formed, these inclusions interact with the red cell membrane and shorten red cell survival, leading to anemia and increased erythroid production.

Types of Beta Thalassemia the lack of beta protein is not great enough to cause problems in the normal functioning of the hemoglobin. A person with this condition simply carries the genetic trait for thalassemia and will usually experience no health problems other than a possible mild anemia. Thalassemia Minor or Thalassemia Trait.

Types of Beta Thalassemia lack of beta protein in the hemoglobin is great bone deformities enlargement of the spleen patients with thalassemia intermedia need blood transfusions to improve their quality of life, but not in order to survive. Thalassemia Intermedia. This is the most severe form of beta thalassemia complete lack of beta protein in the hemoglobin causes a life- threatening anemia requires regular blood transfusions and extensive ongoing medical care. lead to iron-overload which must be treated with chelation therapy Thalassemia Major or Cooley's Anemia.

Inheritance Pattern for Beta Thalassemia

CLINICAL MANIFESTATIONS If not treated, children usually become symptomatic as a result of progressive hemolytic anemia, with profound weakness and cardiac decompensation during the 2nd 6 mo of life. Most infants and children have cardiac decompensation when the hemoglobin is 4.0 g/dL or less.

Summary Number of affected genes Hemoglobin (g/dL) MCV (fL)Transfusion dependent Alpha Thalassemia Alpha-thal-2 trait1NORMALNoneNo Alpha-thal-1-trait2>10<80No Hemoglobin H37-10<70+/- Hydrops Fetalis4Incompatible with Life Beta-Thalassemia Beta-Thal Minor (trait) 1>10<80No Beta-Thal intermedia /- Beta-Thal Majot2<7<70yes

DESFEROXAMINE INDICATION - for the treatment of chronic iron overload due to blood transfusion (transfusional hemosiderosis GOAL - iron chelation therapy - removed the amount of iron administered in transfusion INDESIRABLE EFFECT GI disturbance 26% Skin rash 7%