HemoglobinopathiesPresented by: Dr. Ashwani KoulModerator: Dr Wilson

Sickle Cell DiseaseSickle hemoglobin is the most common abnormal haemoglobin found in the unitedStates (approximately 8% of the african-american population has sickle cell trait)

Genetics

• autosomal co-dominant• Homozygotes (two abnormal genes, SS) do not synthesize haemoglobin A (Hb

A);beyond infancy, red cells contain .75% haemoglobin S (Hb S).• Heterozygotes (one abnormal gene), sickle cell trait, have red cells containing

20–45%Hb S.• Sickle cell trait provides selective advantage against Plasmodium falciparum

malaria(balanced polymorphism).• Thalassemia (frequency of one or two gene deletions is 35% in African-

Americans) may be co-inherited with sickle cell trait or disease. • Individuals who have both thalassemia and sickle cell disease-SS tend to be less

anaemic than those who have sickle cell disease-SS alone.

Pathophysiology

• Hemoglobin S arises as a result of a point mutation (A–T) in the sixth codon of the β-globin gene on chromosome 11, which causes a single amino acid substitution • (glutamic acid to valine at position 6 of the β-globin chain)• Hemoglobin S is more positively charged than Hb A and hence has a

different electrophoretic mobility.• Deoxygenated hemoglobin S polymerizes, leading to cellular

alterations that distort the red cell into a rigid, sickled form

Pathophysiology

Vaso-occlusion with ischemia–reperfusion injury is the central event, but the underlying pathophysiology is complex, involving a number of factors:1. Sickle cells are prematurely destroyed, causing hemolytic anemia2. Intravascular hemolysis reduces nitric oxide (NO) bioavailability by

the following mechanisms

Pathophysiology

Pathophysiology

• NO normally regulates vasodilation, causing increased blood flow and inhibits platelet aggregation. Thus, reduced NO bioavailability is thought to contribute to vasoconstriction and platelet activation• Adhesion molecules are overexpressed on sickle reticulocytes and

mature red cells. Increased red cell adhesion reduces flow rate in the microvasculature, trapping red cells contributing to vaso-occlusion• Sickle cells increase blood viscosity, which also contributes to vaso-

occlusion

Pathophysiology

• Sickle red cells may damage the endothelium leading to production of inflammatory mediators. Ischemia–reperfusion also causes inflammation• White blood cell counts are often elevated in sickle cell disease and

these white cells have increased adhesive properties. White blood cells adhere to endothelial cells and may further trap sickled red cells, contributing to stasis• Activated platelets may interact with abnormal red cells, causing

aggregation and vaso-occlusion• Hemoglobin F affects HbS by decreasing polymer content in cells

Clinical Features

Hematological

Acute ComplicationsChronic Complications and End-Organ

Damage

Hematological

• Anemia• MCV• Reticulocytosis• High platelet count• Neutrophilia• Blood smear – sickle cells (not in infants or others with high Hb F) increased

polychromasia, nucleated red cells and target cells (Howell–Jolly bodies may indicate hyposplenism)• Erythrocyte sedimentation rate (ESR) – low (sickle cells fail to form rouleaux)• Hemoglobin electrophoresis – hemoglobin S migrates slower than hemoglobin A.

Acute Complications-Vaso-occlusive pain event (VOE)

• Episodic microvascular occlusion at one or more sites resulting in pain and inflammation.• Incidence of pain episodes……….• Most common sites.. Hands – Dactylitis( <3-5yrs), Bone(>5yrs),

Abdomen.• Management…• Pain phases..

Acute Complications- Acute chest syndrome• the most common cause of death and the second most common cause of

hospitalization. • It is defined as the development of a new pulmonary infiltrate accompanied

by symptoms including fever, chest pain, tachypnea, cough, hypoxemia and wheezing• Infection(50%)- (Viruses- Parvovirus B19, atypical bacteria mycoplasma

chlamydia) , infarction and/or fat embolization.• Risk is directly proportional to Hb and WBC count. More common in those

with Asthma. Hb F- Protects.• MC involves the left lower lobe, f/b bilateral lower lobes.• Management:

Acute Complications

• Vaso-occlusive pain event (VOE)

Acute Complications- Stroke

• Usually infarction.. Hemorrhagic usually in older children• Prevalence 11%. Highest incidence in 1st yr of life( 1.02 per 100

patient years in 2-5yrs and 0.79 per 100 patient yrs in 6-9)• Risk Factors for Overt Stroke

Goal is to reduce HbS to <30%And to increase Hb to approx 10g%

Chronic Complications- Stroke.. Moya Moya• Prevention of recurrent stroke• RBC transfusions- maintain HbS <30% and after 3-4yrs upto 50%• Fetal Hb stimulating agents – Hydroxyurea• Stem Cell transplantation• Revascularization procedures• Prophylactic Asprin (double edged sword)

• Rehabilitation• Primary stroke Prevention

Screening• Transcranial Doppler (TCD) ultrasonography • • The highest time-averaged mean velocity (TAMMvel) in the distal internalcarotid artery (ICA), its bifurcation and the middle cerebral artery (MCA)are used to categorize studies into the following risk groups.- Normal (velocity ,170 cm/s), low risk- Conditional (170–199 cm/s), moderate risk- Abnormal ($200 cm/s), high risk- Inadequate – unable to obtain velocity • - Very low velocity (ICA/MCA velocity ,70 cm/s) may indicate vessel stenosis and increased risk of stroke• Transfusion should be considered for children with ACA velocity 200 cm/s, especiallyif silent infarcts and/or cerebral blood vessel stenosis are present onMRI/A.• 2 to 16 years.. Annually• Depending on the last TCD..

Chronic Complications- Stroke Prevention• Treatment:• Chronic transfusion to maintain HbS< 30% reduces the risk of stroke by >90%

in children with abnormal TCD• Stem cell Transplantation• Hydroxyurea therapy- decreases TCD velocities( yet under study)

Acute Complications- Priapism

• Sustained painful, involuntary erection for more than 30mins• May be prolonged for >3hrs • Upto 30-40% patients with Sickle cell disease..• Often occurs early morning( Nocturnal acidosis, dehydration)• Triggers: Cold Exposure, Dehydration, Full Bladder, Prolonged sexual

activity, Fever• Stuttering Priapism/ Fulminant priapism (3 Hrs)• Treatment:

• Treatment General:• Attempt to urinate• Try warm bath• IV hydration• Opiate analgesia• Sedation with Diazepam/Lorazepam• Urology consult

• Management- fulminant priapism• Detumescence within 30mins• Penile Aspiration and Epinephrine irrigation within 6 hrs of onset• Transfusion/ Top up exchange• Winter Shunt

Splenic Sequestration

• Highest b/w 5 -24months• Splenomegaly- pooling of blood in spleen• Rapid onset pallor fatigue, may have fever. Abdominal pain often• Hb, platelets and wbc all fall• Treatment :

• Monitor vitals and spleen size closely• Fluid bolus 10-20cc/kg• RBC transfusion- in small aliquots 5ml/kg• Pain management

• Prevention:• Splenectomy, if 1 major or 2 minor acute splenic sequestration episodes• For < 2yr transfusion therapy.

Transient Pure Red Cell Aplasia

• No RBC production for 7-14 days• Reticulocytopenia • Platelets and WBC’s normal• Invariably associated with Parvovirus B19 infection• Usually spontaneously terminates in 10 days• Treatment:• Monitor CBC• Transfusions to raise Hb not more than 10g%• Monitor other siblings with sickle cell.. Contagious virus..

Infections

Chronic Complications- CNS

• Acute Strokes/ Silent Strokes.. Only MRI changes, no clinical deficit• Present in 20-35% cases• Neuropsychologic and impaired school performance• May increase in size and convert to overt Stroke• Moya moya changes..• Treatment/ Prevention:• TCD• Transfusion therapy• Hydroxyurea

Chronic Complications- CardioVascular• Due to overload and chronic anemia- 50% have cardiomegaly.• Often will have a systolic flow murmur• Prolonged Qtc, ECHO will show cardiomegaly• Pulmonary Hypertension:• PASP> 35mmHg or TRV( tricuspid regurgitant jet Velocity) > 2.5m/s• 10% children have PAH• ? Altered NO bioavailability/ Hemolysis• Treatment options : RBC transfusions• Sildenafil (but associated with increased vaso occlusive pain eoisodes)

Chronic Complications- Pulmonary

• Reduced PaO2• Nocturnal Hypoxemia• Pulmonary Fibrosis• Asthma

Chronic Complications- Kidney

• Increased Renal blood flow• Enlarged kidneys.. Distorted collecting system on IVP• Hyposthenuria: Urine Concentration defect, • Obliteration of the vasa recta of the renal medulla• Edema- Focal Scarring- Interstitial Fibrosis- destruction of countercurrent

mechanisms• Obligatory urine output upto 2000ml/m2/day• May present as nocturnal enuresis• Rx – DDAVP 10-40ug at bed time

Kidney…

• Hematuria- Papillary necrosis• Renal Tubular Acidification Defect• Increased Urinary Na Loss- Hyponatremia• Proteinuria- Glomerular insufficiency, Perihilar Focal segmental

Sclerosis- renal Failure• Intraglomerular hypertension• If proteinuria > 4-8 weeks – start ACE inhibitors

• Nephrotic Syndrome– steroid use is controversial in them• Chronic renal Failure-

Chronic Complications- Hepato Billiary• Hpatomegaly• SGOT SGPT elevations• Cholelithiasis:• As early as 2yr, upto 30% have gall stones by 18yrs

• Transfusion related Hepatitis- HBV/HCV• IntraHepatic Crisis- Sickling – massive hyperbilirubinemia, severe pain,

elevated Enzymes.• Rapid progression to Multi organ failure• Mostly require Exchange transfusion

• Hepatic Necrosis, portal fibrosis, cirrhosis• Transfusional Overload

Chronic Complications- Bones

• Expansion of Marrow Cavity--------Bone infarcts• Avascular Necrosis

• MC cause of AVN of femur head is Sickle Cell Disease• About 50% are asymptomatic• Xray:

• Subepiphyseal lucency wide joint space• Flattening or fragmentation of Epiphysis• MRI helps before scarring develops

• Treatment- Supportive- Bed Rest, NSAIDS. Transfusion Doesn’t Help• Core DeCompression - helps early stages• Hip Replacement – may be required in late, but 30% require revision within 4.5 yrs

• Widening of medullary cavity- hair-on-end- Skull X ray• Fish Mouth Vertebrae on X ray Spine

Chronic Complications- Eyes & Ears

• Retinopathy..• Proliferative –

• Sea Fans Clusters- of neovascular tissue• Non Proliferative – doesn’t need treatment.

• Angioid Streaks – pigmented striae in fundus• Hyphema- blood in anterior chamber• Conjunctivae- comma shaped blood vessels• Sensori- neural Hearing loss - 12%• Skin Ulcers- rare before 10yrs

Chronic Complications- Growth and Development• Birth weight is normal• By 2-6 yrs both ht and wt delay. Weight more than height• Increased caloric requirement• Zinc Deficiency• Delayed sexual Maturation- tanner 5 by 17.5 yrs • Decreased fertility and abnormal sperm motility.• Zinc 220mg/day

Chronic Complications-Functional Hyposplenism• By 6 months, spelenomegaly is apparent..• Progressive fibrosis and auto splenectomy• 300-600 times more likely to develop overwhelming pneumococcal

and H influenza sepsis.• Demonstration by: • howel Jolly bodies• Tc 99 Gelatin sulphur scan- no uptake• Pitted RBC > 3.5%

Diagnosis of Sickle Cell Disease

• IN Utero- Mutation Analysis of DNA – chorionic villus biopsy/ fetal fibroblasts obtained by amniocentesis• New born: electrophoresis by• Iso electric focusing• High perf. Liq Chromatography• Citrate Agar- pH 6.2 separates Hb S A and F• DNA based mutation analysis• Guthrie cards

Prognosis

• Survival time is unpredictable• 85% survive beyond 20yrs with active management• Causes of death• Infection- sepsis, meningitis- peak 1-3 yrs age• ACS• Stroke• Organ Failures

Management

• Prevention of complications• Infection- Penicillin Prophylaxis starting 3-4 months of age• 125mg BD <3yrs/ 250mg BD >3yrs• If allergic/ not tolerating Erythromycin 10mg/kg• Give till atleast 5 yrs age

• Immunization-• Routine- with H influenza and 7 valent PCV • 24 valent PCV at 2 yrs and 5 yrs• Meningococcal vaccine 2 yrs• Influenza vaccine yearly

• Treatment of complications • Transfusion therapy• Induction of Fetal Hemoglobin

Transfusions in Sickle cell Anemia

• RBC phenotype at diagnosis• Match For Rh and Kell antigens.• 17.6% alloimmunization incidence

Hydroxyurea (HU)

• Sustained HbF >20% is associated with Reduced clinical severity.• Upregulates HbF, Interferes with HbS polymerization- decreases sickeling, increase RBC

hydration, decrease RBC adhesion• Reduces VOE, ACS, Reduces mortality• Approved for children above 2 yrs• Start at 15-20mg/kg/day increase every 8 weeks by 5mg/kg to max 35mg/kg/day or a

favourable response• Toxicity-

• N <1000• Plat < 80000/mm3• Hb drop by 2g%• Retic Count < 80000/mm3

• Response – rise in HbF by 10-20% Hb rises by 1-2g%

Stem Cell Transplant

• Availability of a matched donor• SCD SS or SCD SB• Complications: • Stroke or CNS event > 24hrs• Recurrent ACS > 2 /yr• Recurrent VOE debilitating• Sickle nephropathy• AVN of multiple joints

Sickle cell Trait

• Indices are normal• Elecrophoresis – AS pattern- Hb A 55-60% Hb S- 35-45%• Usually asymptomatic

Hemoglobin C/CC/AC/SC/E

• HbC- rhomboid crystals with increase osmolality• Lysine for Glutamic acid mutation

• HbE – alternate splice site which leads to decreased production• Mild anemia, mostly asymptomatic, may have target cells on CBP

Unstable Hemoglobins

• Substitutions within the Alpha or Beta chain, esp in the region of heme attachment• Changes in Oxygen affinity occur.. Increase or decrease..• Hemoglobin Chesapeake- clinically as mild polycythemia

ThalassemiaAre a group of disorder where in there is decreased production of globin chains.Deficient Beta globin chains- Beta thalassemiaDeficient Alpha globin chains- Alpha thalassemia

In Next Class.. To Be Continued…..