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    Add as FriendHemoglobinopathies

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    1 : HEMOGLOBINOPATHIES Dr. Neelakshi Kalita Junior Resident NKP Salve Institute of Medical Sciences,Nagpur India
    2 : INTRODUCTION Hemoglobin in RBC is critical for normal oxygen delivery to the tissues. Hemoglobinopathies are disorders affecting structure , function or hemoglobin production. Inherited disorders vary with severity ranging from asymptomatic laboratory abnormalities to death in utero. Can present as hemolytic anaemia,erythrocytosis cyanosis, or vasoocclusive stigmata.
    3 : RED BLOOD CELLS Major function is to transport hemoglobin(Hb) , Hb carries oxygen from lungs to the tissues. Normal RBC - biconcave discs,mean diameter 7.8 micrometer,thickness 2.5 micrometer. Average volume – 90-95 cubic micrometers. Red cell membrane – trilaminar structure , with bimolecular lipid layer between 2 layers of protein.
    4 : PRODUCTION OF RBC. Early weeks of gestation – yolk sac Middle trimester – liver also spleen ,lymph nodes Last month of gestation and after birth – bone marrow Till 5 yrs of age – marrow of all bones After 20yrs – marrow of membranous bones
    6 :
    7 : ERYTHROPOIESIS Stimulus for RBC production in low O2 states is hormone erythropoetin,it is a glycoprotein , mol wt 34,000 90% produced in kidneys, remainder in liver Stimulates proerythroblast production in bone marrow.Speeds production of new RBCs. Nutritional requirements : metals – iron,cobalt,manganese vitamins – B12, folate,Vit C,E,B6, riboflavin amino acids hormones – androgens ,thyroxine
    9 : Hemoglobin Multi-subunit protein (tetramer) 2 ? and 2 ? subunits Heme One per subunit Has an iron atom Carries O2
    10 : Embryonic hemoglobin – 2 alpha + 2 epsilon chains Fetal hemoglobin - 2 alpha + 2 gamma chains Hemoglobin A - 2 alpha + 2 beta chains Hemoglobin A2 - 2 alpha + 2 delta chains Adult red cell – contains mixes of Hb A 95-98%, HbA2 2-3%, Hb F < 2%. Neonates Hb F predominates.
    11 : CLASSIFICATION OF HEMOGLOBINOPATHIES 1) STRUCTURAL HEMOGLOBINOPATHIES Abnormal polymerization- Sickle cell disease Altered oxygen affinity – polycythemia Readily oxidized – unstable hemoglobins, methemoglobinemia 2) THALASSEMIAS Alpha thalassemia Beta thalassemia Alpha-beta,delta-beta,gamma-delta-beta thalassemia 3) THALASSEMIC HEMOGLOBIN VARIANTS HbE Hb constant Spring Hb Lepore
    12 : CLASSIFICATION CONTINUED 4) HEREDITARY persistence of fetal hemoglobin 5) ACQUIRED HEMOGLOBINOPATHIES Methemoglobinemia Sulfhemoglobinemia Carboxyhemoglobinemia Hbh in erythroleukemia Elevated HbF in erythroid stress,bone marrow dysplasia
    13 : DEFECTS OF HEMOGLOBIN SYNTHESIS Qualitative disorders: Structural abnormality in Hb synthesis.E.g sickle cell syndrome etc Quantitative disorders: Decreased synthesis of Hb chain.E.g Thalassemias. Heterozygous state: Sickle cell trait: Benign state ( AS) of HbS, one abnormal gene is inherited. Severe hypoxia leads to symptoms. Sickling occur at PaO2 < 20 mmhg. Diagnosis by: demonstration of sickling Hb electrophoresis
    14 : Homozygous state : Sickle cell anaemia An abnormal gene is inherited from each parent. SS is associated with – decreased life expectancy PaO2 < 40 mm hg can cause sickling
    15 : Historical aspects of sickle cell disease Known to people from West Africa for several centuries. Earliest paper describing SCD in the West was published in 1846 in the Southern Journal of Medical Pharmacology. 1st case described in literature is a Caribbean dental student named Walter Clement Noel reported in 1910 by Dr James Herrick. Mason gave the term Sickle cell anaemia in 1922. Defective gene evolved years ago in parts of Africa,Mediterranean,Middle East,India People with sickle cell trait survived malaria outbreaks
    16 : PATHOPHYSIOLOGY OF SICKLE CELL ANAEMIA SCAN Pathogenesis of sickle cell disease
    17 :
    18 : FACTORS AFFECTING RATE OF SICKLING Amount of HbS and its interaction with other Hb chains Rate of HbS polymerization depends upon Hb concentration Decrease in Ph – increased tendency for sickling Sluggish blood flow in microvascular beds More extensive sickle cell formation in veins Decreased body temperature causes vasoconstriction,leads to sickling. Increased blood viscosity due to dehydration
    19 : CLINICAL MANIFESTATIONS OF SICKLE CELL ANAEMIA Most common, vaso-occlusive crisis Pain crisis – due to intravascular sickling and tissue infarction. Provocative factors – infection, fever, excessive exercise,anxiety,abrupt temperature change,hypoxia Pain can develop in any part of the body,lasts few hrs upto 2 weeks. Areas-lumbosacral spine,knee,shoulder,elbow,femur Leads to aseptic necrosis,of humerus and femural head,chronic arthropathy,osteomyelitis due to Salmonella mainly.
    20 : Hand foot syndrome Painful infarcts of digits with dactylitis Occurs in < 5yrs,small bones of hands and feet involved. Manifests as: fever,puffy,tender,warm feet ,hands Leukocytosis 20,000 – 60,000 cells/cu mm. Radiograph – after 1-2 weeks, subperiostal new bone, cortical thinning,short digits
    21 : Dactylitis
    22 : Acute Chest Syndrome Medical emergency with mortality around 10%. Reflects in situ sickling within lung with microinfarction producing pain,temporary pulmonary dysfunction. Presents with – fever,cough,hemoptysis ,pleuritic chest pain, arterial hypoxemia,pulmonary hypertension, lung infiltration of bases,rib infarcts Recurrent episodes – pulmonary fibrosis,respiratory insufficiency.
    23 : Management: Oxygen supplementation Ventilation support with continuous positive airway pressure Mechanical ventilation Bronchodilators Emperical antibiotics Exchange transfusion to lower HbS concentration Inhaled nitric oxide Treatment of choice – exchange transfusion
    24 : Acute abdominal pain Due to mesenteric sickling,vertebral disease with nerve root compression Mimics acute surgical conditions Right upper quadrant pain with hepatomegaly, unconjugated hyperbilirubinemia,abnormal enzymes Pigment gallstones
    25 : Acute Central Nervous System Event Acute brain infarction in 5 – 10 yrs age Lesion – internal carotid artery stenosis or obstruction,middle cerebral or anterior cerebral artery obstruction. Intracranial hemorrhage Manifests as : severe headache, vertigo, nystagmus, neck pain, ptosis, menengismus
    26 : Hemolytic crisis Characterized by rapidly developing anaemia, leokocytosis, jaundice and fever. Vicious circle of events – low oxygen tension in tissues causes sickling, leads to ruptured red cells, which causes a further decrease in oxygen tension and still more sickling and red cell destruction. Serious decrease in red blood cells within a few hours Characteristic finding – reticulocytes in peripheral smear, fragmented RBCs
    27 : Acute Splenic Sequestration Crisis Defined by decrease in Hb by 2gm/dl from steady state Hb concentration,erythropoesis,acutely enlarging spleen Due to intrasplenic trapping of red cells,erythrostasis leads to tissue hypoxia,thrombosis,infarction,fibrosis Continuous scarring-- shrinkage of spleen, fibrous tissue remains called Autosplenectomy 1st attack between 3months - 5yrs age Manifests as: sudden weakness, pallor, tachycardia, tachypnea, abdominal fullness Risk of infection by Streptococcus pneomoniae
    28 : Aplastic Crisis Decreased red cell survival is compensated by 6-8 fold increase in bone marrow output. Temporary cessation of marrow activity due to viral or bacterial infections causes hematocrit to fall by 10-15% / day. Organ involvement: Retina: vessel occlusion – hemorrhage, - neovascularization,detachments Priapism: due to involvement of penile venous outflow tracts. - permanent impotence is a frequent consequence
    29 : Kidney: papillary necrosis,renal failure Heart: occlusion of intramural coronary arteries - left artium, both ventricles are dilated. - effort dyspnea, cardiomegaly, arrhythmias Manifests as: - left ventricular hypertrophy - ischaemia - sudden death
    30 : Leg ulcers: Chronic painful problem. Area around malleoli involved mostly, delayed healing due to poor circulation. Immunity: Opsonin abnormality seen in children due to decreased IgG Susceptibility to Strep - pneumoniae, H influenzae, Neisseria menengitidis, Salmonella infections Leg ulcer
    31 : Pregnancy outcome: increased incidence spontaneous abortions,IUGR, premature labor postpartum infections. complications increase in pregnancy Pregnancy outcome unaffected by sickle cell trait.
    32 : DIAGNOSIS Full blood count: Hb level low,between 6-9 g/dl 2. Peripheral smear: sickle cells,Howell jolly bodies, sideroblasts. target cells Sickling test: Hb electrophoresis: HbS pedominates,No normal HbA, HbF present around 2-20% Hemoglobin HPLC: for identification and quantification of variant Hb as well as HbA2 , HbF DNA analysis: for defining the mutation Serum urea,creatinine,electrolytes: to assess renal function Liver function tests: deranged liver enzymes,unconjugated bilirubin is increased 9. ECG:for evidence of cardiac damage 10. Chest X-ray: cardiac size, lung fields 11. PFT,ABG,Echocardiography,neurologic imaging
    33 : Blood film of a patient with sickle cell disease Low magnification High magnification showing an irreversively sickled cell, target cells
    34 : MANAGEMENT General measures: - regular physical examination - sufficient rest,warmth,increased fluid intake - avoid physical exertion,high altitude - counselling against smoking Painful episodes: - vigorous hydration - NSAIDS,opioids, - patient controlled analgesia,fentanyl patch - massage,local application of heat. - prophylactic hydroxyurea Transfusion: - to decrease HbS concentration to < 30% - urgent transfusion needed in splenic sequestration of blood. Hydroxyurea: in patients with severe symptoms - stimulates production of HbF - increase in HbF prevents formation of HbS polymers,decreases severity of sickle cell disease. - Dose – 10-30 mg /kg per day.
    35 : RECENT ADVANCES Bone marrow transplantation - - in < 16 yrs, to treat sickle cell anaemia with repeated complications. - can be curative. - barrier is a HLA – matched sibling as donor - expensive, not widely available Anti-tumor drug - 5-deoxyazacytidine in low dose, increases HbF with acceptable toxicity. Gene therapy - under study ,to inactivate sickle gene, - increase expression of gene for HbF Cord-blood stem cells - Arginine butyrate - increase fetal Hb production Poloxamer 188 - to reduce length of pain crisis Nitric oxide - to manage acute chest syndrome
    36 : MANAGEMENT OF ANAESTHESIA Anaesthesia and surgery represent a special risk Goals : - prevent sickle cell crisis - improve patient’s condition pre-operatively - avoid hypoxia,acidosis,hypotension,dehydration hypothermia perioperatively,(5 H ) GENERAL MEASURES HYDRATION: Intravascular dehydration increases Hb concentration ,increases sickling rate Pre-operative fasting guidelines shortened to 2 hrs for clear fluids Prevention of circulatory stasis with intravascular fluid infusion Paucity of definite clinical observation
    37 : TRANSFUSION: Blood transfusion considered with Hb <7g/dl, major surgery,anticipated blood loss. Transfusion indicated to augment oxygen carrying capacity,dilute sickle cells with normal HbA cells Transfusion should be slow,avoid viscosity Extensive cross-matching to prevent alloimmunization OXYGENATION: Hypoxia is a trigger No evidence to support hyperoxygenation or prolonged oxygen beyond required level to maintain baseline oxygen saturation.
    38 : THERMOREGULATION: Hypothermia induced crisis is due to vasoconstriction Warm environment,warming of inspired gases with a humidifier No publication to demonstrate a direct link In sickle cell trait no added risk ACID- BASE REGULATION: Acidosis precipitates complications Increased sickling with decrease in PH Theoritical benefit of sodium bicarbonate administration TOURNIQUET USE: Hazards include – localized circulatory stasis,acidosis, hypoxia, precipates sickle cell formation
    39 : GENERAL ANAESTHESIA Pre-operative physiotherapy and breathing exercises Premedication – anxiolytics prferred to opioids Pre-oxygenation Avoid hypotension on induction Controlled ventilation,ensure normocarbia Close monitoring ,with pulse oximetry,NIBP,ECG, end tidal CO2 , Replace fluid loss promptly,monitor urinary output Dextran 40 to improve microcirculation Minimise venous stasis,problematic in prone position Warm environment
    40 : REGIONAL ANAESTHESIA BENEFITS: - Peripheral vasodilatation secondary to sympathetic block - improved analgesia in immediate post- operative period DISADVANTAGES: - can cause hypotension, hypoperfusion - compensatory vasoconstriction & decreased PaO2 in unblocked areas making them vulnerable to infarction
    41 : LAPAROSCOPIC SURGERY Minimally invasive surgery reduces the high mortality and morbidity associated with surgery in this high risk group Studies have been conducted which shows the safety of laparoscopic procedures Some recommendations which are suggested Patients should be jointly managed by experienced surgeons and anaesthesiologists Patients should be admitted at least 3 days prior to surgery to determine and organise the need for simple or exchange tranfusion. Adequate hydration night before surgery with IV fluids DVT prophylaxis with SC Heparin(5000 U) with premedication,continued post –op TDS till patient is ambulatory
    42 : Prophylactic antibiotics with induction of Anaesthesia continued post operatively. Special precaution in introducing the Verees needle and trocars to avoid iatrogenic injury to an enlarged spleen Factors that trigger a vaso – occlusive crisis should be avoided like dehydration,acidosis,hypothermia,sepsis There should be adequate analgesia, oxygenation, hydration, early mobilization postoperatively Large amounts of opiate analgesia should be avoided
    43 : POST – OPERATIVE PERIOD PRECAUTIONS TO DECREASE RISK OF SICKLING Careful monitoring of vital signs,level of conciousness Ensure clear airway,oxygen supplementation Proper reversal of neuromuscular blockade Before extubation 100% oxygen for 2-3 minutes Chest physiotherapy Adequate analgesia,regional and local blocks Maintenance of intravenous fluid till oral intake
    44 : THALASSEMIA SYNDROMES Heterogenous group of inherited disorders Genetic lesions leads to decreased synthesis of either alpha or beta - globin chain of HbA BETA THALASSEMIAS Diminished synthesis of structurally normal beta- globin chains unimpaired synthesis of alpha- chains MOLECULAR PATHOGENESIS: - HbA- tetramer of 2alpha,2beta chains encoded by a pair of a- globin genes on chromosome 16 and a single b-globin gene on chromosome 11 resp. - B0 – thalassemia- total absence of b- globin chains - B+ -- thalassemia- reduced b-globin chains - most are point mutations
    46 : THALASSEMIA MAJOR : - Homozygous for beta-thalassemia genes. - Severe transfusion dependent anaemia THALASSEMIA MINOR /TRAIT : - Heterozygous with 1 beta-thalassemia gene and 1 normal gene - mild hemolytic anaemia,no symptoms BETA-THALASSEMIA INTERMEDIA - intermediate form
    47 : THALASSEMIA MAJOR (COOLEY’S ANAEMIA) In 1925 Thomas B Cooley gave the first description of severe thalassemia . 1st case in India reported by Dr Mukherjee in 1938. Common in Mediterranean countries,parts of Africa,Southeast Asia.In India common among Sindhis,Kutchis,Lohanas,Bhanushalis,Mahars, Punjabi communities. Anaemia manifests 6-9 months after birth as Hb synthesis switches from HbF to HbA. Hb levels remain low between 3-9 g/dl
    48 : Clinical features: Child presents in 1st yr of life with lethargy,poor feeding,recurrent infections,massive bone marrow expansion,delayed growth and development. Characteristic facies –chipmunk ,with maxillary marrow hyperplasia, frontal bossing Pathological fractures of long bones. Hemolytic anaemia - - hepatosplenomegaly Cardiac problems - - secondary to iron overload, cardiomegaly,l eft ventricular overload, heart failure, arrhythmias Endocrine -- diabetes mellitus, hyperthyroidism, hypogonadism, hyperparathyroidism Gout, jaundice, cirrhosis of liver,hepatocellular carcinoma Spinal cord compression -- epidural extramedullary hematopoiesis,vertebral fractures Hemolytic Facies
    50 : THALASSEMIA MINOR: Resistance against falciparum malaria Asymptomatic,mild anaemia Mild erythroid hyperplasia in bone marrow ALPHA – THALASSEMIAS: Reduced or absent synthesis of alpha-globin chains Normally 4 alpha-globin genes present 4 types of clinical syndromes: Silent Carrier State - single alpha-globin gene deleted, Barely detectable reduction in alpha-globin chain synthesis Completely asymptomatic Alpha-thalassemia trait- 2 alpha-globin gene deletion No anaemia,no physical signs,like b-thalassemia minor
    51 : Hemoglobin H Disease- 3 alpha-globin gene deletion HbH most common among Asians Synthesis of alpha chains decreased,tetramers of excess beta -globin called HbH form HbH – extremely high affinity for oxygen, - tissue hypoxia, - prone to oxidation,intracellular inclusions form,Heinz bodies - precipitates of oxidised HbH form - moderately severe anaemia Hydrops Fetalis- all 4 alpha-globin gene deletion In fetus excess gamma globin chains form tetramers (Hb Barts),very high affinity for oxygen No oxygen delivery to tissues Fetal distress by 3rd trimester,IUD results Fetus – pallor, generalized edema, massive hepatosplenomegaly Intra-uterine transfusion can save such infants
    52 : DIAGNOSIS OF THALASSEMIAS Thalassemia major Diagnosed in childhood – severe anaemia Hb ,3-6g/dl characteristic facies with fronto-parietal & occipital bossing malar prominence,malocclusion of teeth Hepatosplenomegaly Peripheral smear – anisocytosis,poikilocytosis, hypochromia,target cells,fragmented RBCs Increased reticulocytes 2-4% Hb electrophoresis- Lack of HbA, elevated HbF, HbA2 Iron studies – increased serum iron level & ferritin WBC- increased, Platelets – normal or decreased MCV, MCH, MCHC significantly decreased Skull X-ray – characteristic hair on end appearance HPLC – to identify Hb variants Prenatal diagnosis possible – by molecular analysis of DNA
    53 : Beta- Thalassemia minor/trait Mild anaemia Microcytosis,hypochromia,target cells Hb electrophoresis – HbA2,HbF increased Alpha- Thalassemia trait Mild hypochromia,micrcytosis without anaemia MCV,MCHC,MCH slightly decreased
    54 : MANAGEMENT OF THALASSEMIAS Chronic transfusion therapy- maintain hematocrit at 25-30% to suppress erythropoiesis, prevent anaemia Splenectomy- in splenomegaly with hypersplenism signs & child is >5yrs of age Prophylactic penicillin therapy continued life – long. Folic acid supplement – 1 mg /day Chelation therapy- prevention and treatment of iron overload Vaccination against Pneumococcus Bone marrow transplantation Cord blood transfusion Gene therapy – insertion of normal genes in the stem cells of recepients PREVENTION Antenatal diagnosis possible Amniocentesis,chorionic villus biopsy Genetic counselling
    55 : ANAESTHETIC IMPLICATIONS Anaesthetic literature is scant Anaesthesia required for various surgeries Airway access difficult due to malar prominence, difficult intubation Maintenance of hemodynamic stability Laparoscopic techniques employed for splenectomy , cholecystectomy Blood loss managed with cell salvage technique
    56 : METHEMOGLOBINEMIA Acquired hemoglobinopathy Methemoglobin is HbA where iron exists in ferric rather than normal ferrous form Ferric form- unable to bind with oxygen, so O2 carrying capacity of arterial blood decreased Shifts oxyhemoglobin dissociation curve to left Normal concentration < 1%, due to methhemoglobin reductase enzyme .Congenital absence predisposes in patients receiving nitrate containing compounds Diagnosis: Hypoxic patient with cyanosis,normal Pao2 Pulse oximetry – decrease in Spo2 with normal Pao2
    57 : Symptoms of: Lethargy,dizziness,headache Characteristic muddy appearance of freshly drawn blood Diagnostic test of choice – methemoglobinemia content Treatment – Methylene blue 1mg/kg IV over 5 mins,dose can be repeated every 60 mins if cyanosis persists > 7mg/kg can oxidize Hb to methemoglobin
    58 : SULFHEMOGLOBINEMIA Rare cause of cyanosis,drug induced,oxidation of iron in Hb occurs due to drugs Nitrate containing compounds,metoclopramide therapy can cause Sulfhemoglobin cannot carry oxygen.High concentration tolerated due to shift of oxyhemoglobin dissociation curve to right. DIAGNOSIS: Decrease in Spo2 values despite normal PaO2 Clinical cyanosis Bluish tinge of freshly drawn blood
    59 : TREATMENT No pharmacological treatment available Only means to remove sulfhemoglobin is eventual destruction of affected RBCs
    60 : CARBOXYHEMOGLOBIN Acquired hemoglobinopathy due to carbon-monoxide poisoning CO has 200times higher affinity for Hb than oxygen,it can displace oxygen and diminish oxygen delivery. Manifests as:dyspnea,headache,nausea,vomiting emotional lability,confusion, impaired judgement Cherry red colour of skin ,mucous membrane Masks development of cyanosis associated with poor oxygen delivery to tissues
    61 : Management: 100% oxygen via a tight fitting mask until CO levels decrease < 10% and symptoms resolve Hyperbaric oxygen in comatose patient with CO level >40%. And in patients with CO levels > 25% who had seizures.
    62 : HEMOGLOBIN C AND E HbC a beta-chain variant Common in West Africa HbE, beta-hemoglobinopathy is common in South East Asia Mild hemolytic anaemia Mild to moderate splenomegaly Can combine with other mutations and produce symptoms of sickle cell disease and thalassemia resp.
    63 : Thank you!
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