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Sickle Cell AnemiaScott Hebert MDApril 24 2017 What is SSD SSD is an autosomal recessive disorder of a.point mutation in the beta globulin chain inhemoglobin https www slideshare net mobi... What is SSD The point mutation in SSD causes a.substitution of valine for glutamic acid as the6th amino acid in the beta globin chain HbS a2bS2 6Glu Val This results in the tetramer A2 B S2 becoming poorly soluble when deoxygenated .resulting in rope like crystallized fibers thatelongate decreasing oxygen carrying capacityand cause distortion of the erythrocyte intothe crescent or sickle shape http www australianhospitals ... . The hallmark symptom of this distortion is avasoocclusive crisis due to decreased oxygen access to heme due to sickling of the erythrocyte microvascularobstruction . increased adherence to endothelium free plasma hemoglobin that scavenge nitric oxide causing vasoconstriction Diagnostic testing Methods of diagnosis of sickle cell disease.vary with the age of the patient Prenatal DNA based testing chorionic villus sampling at 8 to 10 weeks PCR based testing currently of interest in vitro. Diagnostic testing Methods of diagnosis of sickle cell disease vary withthe age of the patient After birth Separate hemoglobin species according to amino acid.composition hemoglobin electrophoresis thin layer isoelectric focusing similar concept toelectrophoresis but the proteins migrate to their pH neutralregions Patterns based on this Capable of higher resolution.with proteins where a single band can be fractionated solubility testing HbS less soluble and forms crystals cloudyappearance when cells are lysed then mixed with a reagent peripheral blood smear Methods of protein based hemoglobin. High performance liquid chromatography HPLC uses pressure and absorbent filled column to separatecomponents based of flow rates out of the column Isoelectric focusing IEF similar concept to electrophoresis but the proteins migrate.to their pH neutral regions Patterns based on this Capableof higher resolution with proteins where a single band can befractionated Capillary electrophoresis performance based on electrokinetic driven separation in.submillimeter diameter capillaries and mirco nano fluidic Electrophoresis cellulose acetate citrate agar electrically driven protein migration through gels Protein based hemoglobin analysisadvantages vs disadvantages. Methods of DNA based hemoglobin GAP PCR amplification using oligo primer flanking deletion breakpoints Traditional DNA sequencing determining precise order of nucleotide within a DNA molecule. Multiplex ligation dependant probe amplification uses forward and reverse probe oligonuclotides that hybridize andligate together to form one target Unbound probes are separated outbefore amplification Next generation DNA sequencing. comprehensive analysis of genome Allele specific oligonucleotide testing targets specific mutation using complimentary DNA to the target Restriction fragment length polymorphism testing measurement of fragments after digestion of DNA samples with.restriction endonucleases DNA based hemoglobin analysisadvantages vs disadvantages The goal of the protein and DNA analysis is to determine thetype of hemoglobin .These are the patterns of common sickle cell syndromes SSD Presentation Patients in the adult population will likelypresent with a history of sickle cell disease assymptoms begin early in life . SSD Presentation SSD Presentation SSD PresentationAcute pain crisis Most common types of vasoocclusive event .Not always a crisis Pain can be a SCD complication in and of itselfor pain can co occur with mask otherpotentially life threatening complications Pain episodes can begin as early as six months.of age and typically last throughout life SSD PresentationAcute pain crisis Patient s report is the gold standard for assessment as there is no combination of physical findings or.laboratory tests that can be used todetermine confirm pain Placebo should never be used as it undermines thephysician patient relationship and lengthens theduration of pain . Pain typically is managed by the patient or family at SSD PresentationAcute pain crisis ED presentations usually when pain can nolonger be managed at home . Pain events are commonly associated with Acute chest syndrome Acute multi organ failure Sudden death syndrome Acute surgical abdomen eg cholecystitis . Acute papillary necrosis Delayed hemolytic transfusion reaction Acute splenic or hepatic sequestration crises Opioid withdrawal SSD Presentation.Chronic Pain Experienced by a large percentage of patients Mechanisms differs from acute pain and may include bone and joint damage chronic ulcers. central sensitization Hyperalgesia altered opioid metabolism Frequent pain may generate feelings of despair depression and apathy that interfere with daily life.and promote an existence that revolves around pain SSD Presentation Viral infections may be more virulent eg parvovirus H1N1 influenza Zika virus Malaria common cause of morbidity and.mortality in children worldwide Infections are a major cause of morbidity and SSD Presentation Mechanisms include functional hyposplenism asplenism. increases risk of encapsulated organisms reduced tissue perfusion presence of an indwelling catheter central line hypoventilation SSD Presentation. Common sites of infection bacteremia meningitis pulmonary infections pneumonia acute chest syndrome May present with. fever leukocytosis focal findings fever headache meningismus seizures inmeningitis or fever chest pain cough wheezing and orhypoxemia in ACS pancytopenia from bone marrow suppression. signs of DIC prolonged PT aPTT decreased fibrinogen orincreased D dimer SSD PresentationMultiorgan failure Life threatening complication in which multiple organ.systems are affected by ischemia and or infarction Typically seen in the setting of an acute painful The mechanism is incompletely understood Management with prompt and aggressive exchangetransfusion therapy. SSD Presentation Chronic compensated hemolytic anemia withepisodes of acute worsening Contributed by inappropriately low serumerythropoietin and or folate or iron deficiency . Major causes of an acute drop in hemoglobinlevel that are life threatening aplastic crisis splenic sequestration crisis hyperhemolytic crisis. SSD PresentationChronic compensated hemolytic anemia Sickled cells undergo hemolysis with a lifespan ofapproximately 17 days Compensatory increases in RBC production and.adaptation to a lower hemoglobin level Typical findings hemoglobin 8 to 10 g dL hematocrit 20 to 30 percent polychromasia and reticulocytosis retic 3 15 . sickled cells Howell Jolly bodies mildly increased WBC count normal RBC indices unless coexistence of thal iron def Markers may be less severe in pts receivingtransfusion therapy or hydroxyurea. SSD PresentationAplastic crisis Acute drop in hemoglobin level caused by atransient arrest of erythropoiesis Managed with transfusion. SSD PresentationSplenic sequestration crisis Acute drop in hemoglobin 2 2 vasoocclusionwithin the spleen and splenic pooling of RBCswhich can lead to hypovolemic shock and. Occurs in spleens that have not yet becomefibrotic due to repeated splenic infarction Infants sickle variants most often affected Rapidly enlarging spleen decreasedhemoglobin despite persistent reticulocytosis. Splenectomy after the first acute event toprevent recurrence SSD PresentationNeurologic complications Stroke and TIA. without intervention 11 percent patients withclinically apparent stroke by 20 yrs 25 by 45 ischemic stroke is more children hemorrhagicmore common in adults primary prevention to reduce the risk of a first.stroke based on the use of regular transcranialdoppler measurements for risk stratification in atrisk pediatric patients previous stroke warrants chronic prophylactictransfusions to prevent recurrent stroke . SSD PresentationNeurologic complications Seizures 2 3x more common in SCD Posterior reversible encephalopathy. less common can mimic stroke SSD PresentationPulmonary complications Facilitate sickling with low oxygen tension and Acute and chronic complications. acute chest syndrome fever chest pain hypoxemia wheezing cough orrespiratory distress cause is often multifactorial and includes infection vasoocclusion hypoventilation atelectasis .thrombosis or thromboembolism and in somecases fat embolism SSD PresentationPulmonary complications Management includes analgesia oxygen .incentive spirometry bronchodilators antibiotics and transfusion Preventive approaches to reducing the risk ofACS include prophylactic antibiotics and immunizations. Hydroxyurea transfusions for recurrent ACS episodes despitehydroxyurea consideration of hematopoietic cell transplantationfor those with an available donor. SSD PresentationPulmonary complications Asthma Sleep disordered breathing Pulmonary fibrosis. Thromboembolic disease Pulmonary hypertension 6 to 10 percent of individuals with SCD screening q1 3 yrs SSD Presentation.Skeletal complications Dactylitis in infants children Osteoporosis Avascular necrosis Osteomylitis. SSD PresentationCardiac complications Cardiomyopathy and heart failure due to chronic anemia iron overload . SSD PresentationHepatobiliary complications Acute ischemia Cholestasis Hepatic sequestration crisis. Transfusional iron overload Pigment gallstones Hepatitis C virus SSD PresentationLeg ulcers. Due to compromised blood flow endothelialdysfunction thrombosis inflammation anddelayed healing More common in males than females Post traumatic potentially related to.superinfection Preventative strategies important SSD PresentationRetinopathy Annual screening after age 10. SSD PresentationPregnancy complications intrauterine growth restriction fetal death and lowbirthweight Maternal. acute chest syndrome infections preeclampsia andthromboembolic events Management reproductive counseling birth control folic acid screening for bactiuria and fetal growth cord blood.harvesting prophylactic transfusion postpartumanticoagulation in cesarean delivery SSD Presentation Common serious and under diagnosed SSD Presentation. Hypercoaguable state Thromboprophylaxis in hospitalized patients SSD PresentationGrowth and development Frequently underweight with normal height. Often delayed puberty SSD PresentationPsychosocial issues Most are well adjusted Increased risk of chronic medical condition. low self esteem social isolation poor family relationships withdrawal from normal daily living due toinappropriate pain coping strategies reduced.quality of life anxiety depression andneurocognitive impairment Management Regular clinician follow up Prevention of complications with early.penicillin prophylaxis started in the newbornperiod appropriate immunizations and bloodtransfusions for those at risk for stroke Management Hydroxyurea used to reduce sickle hemoglobin by increasing.the production of fetal hemoglobin Increased HbF production up to 2 fold via shiftin gene expression at the beta globin locus Effects reduce sickeling. increased RBC lifespan improved RBC hydration decreased hemolysis and vascular endothelium improved microcirculation blood flow decreased vasooclusive events . Management Hydroxyurea Other mechanisms decreased hemolysis less nitric oxide scavengingand vasodilation decrased density with more mature RBC s and.easier passage through microcirculation decreased WBC count and neutrophil adhesivenessdecreasing inflammatory pain Hydroxyurea should be started in symptomatic.The pregnancy-related mortality rate in women with sickle cell anemia is between 0.5% and 2%. Because of the associated increased fetal morbidity and maternal mortality, pregnancy in women with sickle cell disease should be managed by a team of medical personnel, including an obstetrician, internist, and hematologist.