1-19-10 Clinical Case Class Discusion: sickle cell disease 1. Describe hemoglobin S polymerization.

Morphologic rbc sickling occurs due to polymerized Hb S !hich has t!o main e""ects: Membrane damage due to fragmentation and oxidant damage: e#posure o" cryptic protein se$uences causes adherence o" %ascular endothelium !hile phosphatidyl serine has a pro-thrombotic e""ect& Moreo%er there is increased membrane rigidity& Intracellular dehydration due to loss of K and H20: dehydration makes the sickled cells %ery dense and are too poorly de"ormable to pass through narro!ed %essels& 'his causes increased %iscosity and reduced blood "lo!& 2. Identify the factors that influence polymerization. Hb S polymerization is promoted by: (educed o#ygen tension)saturation (educed pH *a""ects o#ygen tension+ (educed intracellular hydration ,ncreased temperature Hb S polymerization is inhibited by: Hb 3. Describe the common genotypes of sickle cell diseases. D./ substitution at codon si# o" the beta globin chain: Hb S: glu->%al Hb C: glu->lys Sickle cell anemia occurs !) homozygote *HbSS+ Sickle C disease occurs !) a double heterozygote *HbSC+ S thalassemia occurs !) a double heterozygote *HbS01+ S ! thalassemia occurs !) a double heterozygote *HbS00+ ". #$plain the mechanism that produces the signs and symptoms of this disease. 'he clinical syndromes o" ss Disease are primarily the conse$uence o" %ascular occlusion& .o! it2s actually the less dense rbc2s that adhere to %ascular endothelium in the post-capillary %enule producing partial obstruction to "lo!& Dense cells lodge behind the partial obstruction and "ully occlude the %essel& &ypo$ia occurs !hich reduces o#ygen tension and lo!ers pH to encourage sickling& 'he occlusion spreads retrograde in !hat is kno!n as a 3log 4am5 phenomenon& 'he conse$uences are ischemia infarction and necrosis *mani"esting as acute pain+6&!ith e%entual organ damage)failure or chronic bone pain& ,n addition to occlusion ss Disease produces hemolysis& 7nce thought to be benign hemolysis is no! associated !ith pulmonary hypertension priapism *erect penis+ stroke and leg ulcers& 'he mechanism o" hemolysis in%ol%es Endothelin-1* induced pulmonary arteriolar hyperplasia

and thrombosis from decreased le els of nitric oxide*8 that normally !orks to pre%ent platelet aggregation& 89ndothelin-1 *9'-1+ is a potent %asoconstrictor !hose le%els are increased !ith hypo#emia& 7ne can see 9'-1 le%els rise 4ust be"ore and during acute in"lammatory conditions such as acute chest syndrome& 88.itric o#ide is a potent %asodilator and inhibitor o" adhesi%e reactions among sickle cells leukocytes platelets and endothelium by reducing :C/M-1 e#pression by endothelial cells& ,t is produced "rom ;-arginine and nitric o#ide synthase *i.7S+ in endothelial cells& <ith ss disease ;-arginine le%els are depleted because lysed rbc2s release arginase !hich breaks ;-arginine do!n& Hence there is a drop in .7 synthesis& Moreo%er Hb liberated "rom rbc2s consumes .7 producing methemoglobin and nitrates& /ll these "actors lead to a ma4or drop in .7 that impairs its "unctions in blocking platelet aggregation or regulation o" :C/M-1 ,C/M-1 =-selectin and 9-selectin& 'he net rise in 9'-1 and drop in .7 promote %asoconstriction endothelial acti%ation and proli"eration& '. (ecognize the clinical features of the sickling disorders. Chronic hemolytic anemia: "rom rise in 9'-1 and decrease in .7 *see abo%e+& )cute *ain #pisodes: most o"ten due to marro! ischemia !hich produces poorly localized pain !ith "e! physical "indings& ,t2s a 3genetically ske!ed5 symptom *a small minority o" patients e#perience the ma4ority o" pain crises+ associated !ith decreased sur i al and can be managed !ith analgesics& ," pain is not relie%ed pain crises can precipitate increased muscle tension that !orsens the pain and causes splinting hypo%entilation hypo#ia and pneumonitis& 'hus aggressi%e pain management is key> Infection: this is due to asplenia that occurs primarily in HbSS resulting in septicemia& Ho!e%er septicemia is uncommon !ith prophylactic antibiotic therapy in those under ? y&o& )cute Chest Syndrome: an acute pulmonary in"iltrate !ith cough and "e%er in the lungs& ,t results "rom HbS polymerization and trapping in the lung capillaries that ultimately leads to acute respiratory distress syndrome */(DS+& (esidual "ibrosis "rom the in"lammation)necrosis can lead to progressi%e lung disease !ith chronic hypo#ia and high mortality& +at #mbolism Syndrome: bone marro! necrosis can release marro! elements into the circulation producing a "at embolus that !ill result in abrupt onset o" "e%er tachypnea se%ere hypo#emia and altered mental status& ,t speeds up the progression o" /(DS because o" the in"lammation caused by the marro! "at& 'o break the cycle o" hypo#iaHbS polyemerizationacute chest syndrome)lung disease e#change trans"usion is administered&

,. Discuss the clinical syndromes associated -ith the sickling disorders. 'here are se%eral organ damage syndromes associated !ith sickling disorders: *roliferati%e sickle retinopathy. retinal detachment and blindness *similar to that o" diabetes+& 'here2s earlier onset o" retinopathies in "ic#le $ %isease due to higher Hb concentration and its e""ect on blood %iscosity)"lo!&

)utosplenectomy: due to ischemic necrosis o" the spleen& 7ccurs by @ y&o& in Hb "" and is less "re$uent in other %ariants& (esulting asplenia predisposes the paitent to in"ection !ith encapsulateds like "& pneumoniae' "almonella' H& influen(ae Cholelithiasis: bilirubin stones "rom hemolysis& .ecessitates gall bladder remo%al& )%ascular necrosis of bone: osteonecrosis causes dactylitis in children *acute in"lammation o" digits+ and bony de"ormities& "taph in"ection is commonly "ound in the bones as is "almonella& (enal manifestations: glomerular hypertrophy increased renal blood "lo! and increased glomerular "iltration rate& ,schemia occurs disrupting the counter-current mechanism and causing hyposthenuria *inability to retain !ater+& Such renal insu""iciency shortens patient sur i ial and is associated !ith an increased rate o" complications& 'here is a drop in 9=7 !hich !orsens the anemia& /ortality: median sur%i%al o" HbSS is mid A0s sur%i%al o" HbSC is late B02s& ,n"ection !as the ma4or cause o" mortality in children but no! stro#e and its conse$uences are most signi"icant "ollo!ed by renal "ailure and lung damage&

0. Describe the general therapeutic approaches to the sickling diseases. Supporti%e care: oral),: hydration pain management in"ection prophyla#is)management management o" end-organ complications 1ransfusion: done acutely to treat anemia and hypo#emia and chronically to suppress Hb " production' pre ent stro#e' and other end-organ complications& 'here are risks o" iron o%erload trans"usion reactions alloimmunization and %iral transmission& &ydro$yurea: decreases Hb S polymerization by increasing Hb ) production *3stress erythropoiesis+ and decreasing membrane damage by reducing hemolysis and adhesion& / multi-insitutional study on hydro#yurea demonstrated that it reduced pain crises and reduced pulmonary e%ents *pulmonary in"arcts and "at emboli+ but also had to#icity *cytopenia !eight gain C, upset and hair loss+ and de%elopment o" leg ulcers a"ter ? years o" use& ,n addition to hydro#yurea decitabine and butyrate both increase Hb - le%els& 2one /arro- 1ransplantation: !orks !ell "or patients !ith minimal end-organ damageD results in less gra"t-%s-host disease and "a%orable mortality o" less than1 10E& Ho!e%er re$uires matched sibling donors& 3ene therapy: recently reported success in animal models&