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59 Cards in this Set
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- Back
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hydroxyurea
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drug that induces fetal Hgb production
only FDA-approved agent for the treatment of SCD can improve clinical condition - blocks interaction between deoxy Hgb S molecs also, decrease in white blood cells, platelets, and reticulocytes, improvement in red cell hydration, and a decrease in red cell adhesiveness to the vascular endothelium recommended in patients with three or more vasoocclusive episodes or history of acute chest syndrome start single daily dose of 15 mg/kg, escalated until toxicity or a max dose of 35 mg/kg |
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thalassemias
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mutations that cause decreased production of either the alpha or beta chains of Hgb - imbalance = damage and destruction of RBC
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Hgb C
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results from a mutation in the beta globin gene and is the predominant hemoglobin found in people with hemoglobin C disease
- mild hemolytic anemia - splenomegaly |
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Hb Barts
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four-gene deletion thalassemia and consequent hemoglobin Barts (gamma chains produced during fetal development combine to form gamma chain tetramers)
die in utero from severe tissue hypoxia causing profound edema (hydrops), congestive heart failure (HgH and HgBarts dont release O2, extraordinary O2 affinity) - hypertropic placenta |
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Hgb S
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glutamic acid to valine substitution at the 6th amino acid of the beta-globin chain of human adult hemoglobin (Hb A) (chromosome 11)
<40% of Hgb is HgS = only have trait = essentially symptom free |
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rate and extent of HbS polymerization is dependent on
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intracellular hemoglobin concentration,
presence of hemoglobins other than Hb S, blood oxygen saturation, pH, temperature, 2,3-BPG levels |
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Hgb SS cellular dehydration
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membrane injury results in impaired cation homeostasis
decreased capacity to maintain intracellular potassium net result is loss of intracellular potassium and water resulting in cellular dehydration = increase [Hgb} = favours sickling |
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sickle cell labs
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normocytic, normochromic, hemolytic anemia, sickle cells
^ LDH ^ indirect bilirubin ^ reticulocyte count Hgb 5-11 g/dL Normal MCHC serum EPO low relative to degree of anemia ^ neutrophils, platelets ^ serrum ferritin hyperplasia in marrow |
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vasoocclusive crisis
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most common clinical manifestation (varying hz)
- interplay bw sickled cells, neutrophils, endothelium and plasma factors = tissue hypoxia > tissue death > pain (chest, low back, extremities, abdomen) - fever often present - may be precipitated by dehydration, infection, cold weather (1/2 cases no cause) |
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phases vasoocclusive crisis
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1) prodromal
2) initial, evolving 3) established, inflammatory 4) resolution, recovery |
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aplastic crisis
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cessation in red cell production in the face of ongoing hemolysis resulting in an acute, severe drop in hemoglobin levels
decrease in reticulocyte count <1% ** usually associated w infections (parvovirus B19 attaches to erythroid prog cells = temporary arrest) * rarely reccurent bc Ab * most resolve in 2 weeks |
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parvovirus B19
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can cause aplastic crisis in sickle cell disease
attaches to P Ag receptor of erythroid progenitor cells arresting RBC production develop Ab to clear up in 2 weeks pancytopenia may occur |
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Sequestration Crisis
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sudden, massive pooling of red cells, especially in the spleen, which may result in hypovolemic shock and cardiovascular collapse
typically seen <5yo prior to autoinfarction of spleen minor episode Hgb >7g/dL major Hgb <7g/dL or dropped 3 present with rapidly enlarging spleen or liver, pain, hypoxemia, and hypovolemic shock tx: RBC transfusion, exchange transfusion (careful of hyperviscosity post crisis) |
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Hyperhemolytic Crisis
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episodes of accelerated hemolysis characterized by decreased blood hemoglobin, increasing reticulocytes, and other markers of hemolysis (hyperbilirubinemia, increased LDH)
eg during resolution phase of vasoocclusive crisis |
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pseudoaddiction
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Nonsatisfactory relief of pain drives patients to behaviors that appear to healthcare givers as signs of addiction
see in SCD bc pain is often underrated in its intensity and undertreated by caregivers, especially inexperienced physicians (only 10% addicted, comparable to other disease states) |
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management of pain in SCD
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opioids,
NSAIDs, acetaminophen, or a combo adults and children >50 kg, start morphine dose of 0.1 to 0.15 mg/kg hydromorphone dose: 0.015 to 0.02 mg/kg IV (recommended doses for opioid-naïve patients) Antidepressants, anticonvulsants, and clonidine for neuropathic pain severe, unrelenting pain may require red cell transfusion to decrease sickle cells below 30% |
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acute chest syndrome (ACS)
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constellation of signs and symptoms in patients with SCD that includes a new infiltrate on chest xray defined by alveolar consolidation but not atelectasis, chest pain, fever, tachypnea, wheezing, or cough, and hypoxia
leading cause of mortality in patients with SCD peds: bacteria or viral cause adults: fat mircroemboli from marrow necrosis in crisis |
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pathogenesis of ACS
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increased intrapulmonary sickling,
intrapulmonary inflammation with increased microvascular permeability, and alveolar consolidation |
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treatment ACS
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oxygenation,
incentive spirometry, adequate pain control to avoid chest splinting, antimicrobial therapy that covers atypical bacteria, avoidance of overhydration, application of bronchodilators red cell transfusion to decrease intrapulmonary sickling |
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CV/Resp manifestations of SCD
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pulmonary manifestations
- acute chest syndrome - pulmonary HTN (1/3) - asthma (co-morbid) - abnormal pulm fn test - airway hyperreactivity Cardiac manifestations: - hemodynamic burden = ^CO - hyperdynamic circulation Stroke: ischemic in kids and older adults, hemorrhagic in 30s |
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GU manifestations SCD
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- renal failure
- hematuria - proteinuria, renal tubular acidosis - priapism - nocturnal enuresis |
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Priapism
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potentially harmful and painful medical condition in which the erect penis or clitoris[1] does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours
Low-flow involves the blood not adequately returning to the body from the organ (see in SCD) High-flow involves a short-circuit of the vascular system partway along the organ. "Stuttering" priapism is a term used for episodes that last less than 3 hours but are repetitive |
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Nocturnal Enuresis
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bedwetting
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Dactylitis
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painful swelling of digits of hands and feet ("hand-foot syndrome")
occurs early in infancy as hematopoietic marrow is still present in these bones at this age |
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MSK manifestations of SCD
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Dactylitis
Osteomyelitis and Bone Infarction Osteopenia and Osteoporosis Avascular Necrosis: Vasoocclusion resulting in infarction of articular surfaces of long bone occurs most commonly in the femur followed by the humerus decreased bone mineral density, growth retardation, delayed skeletal maturation in children |
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non CV, GU, MSK manifestations of SCD
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- Leg ulcers
- hepatobiliary: chronic liver abnormalities - retinopathy (leading to blindness) - Functional asplenia defined as impaired mononuclear phagocyte system functions - complications in pregnancy - predisposal to infections |
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proposed subphenotypes of SCD
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hemolysis-endothelial dysfunction: brisk hemolysis
- pulmonary hypertension, leg ulcers, priapism, and possibly stroke viscosity-vasoocclusion subphenotype: higher hemoglobin and hematocrit levels and hence higher blood viscosity - acute chest syndrome, frequent pain episodes, avascular necrosis, and retinopathy not absolute and significant overlap exists; useful for framework in understanding the basic pathophysiologic mechanisms and in designing therapies |
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Hematopoietic Stem Cell Transplantation tx for SCD
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ideally should be done in patients who are likely to have a severe disease course but instituted early, prior to end-organ damage
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Red cell transfusion in SCD
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acute or chronic basis
increasing hemoglobin concentration and thereby increasing oxygen carrying capacity of the blood decreases the percentage of circulating Hb S-containing red cells indications: symptomatic anemia, acute chest syndrome, stroke, aplastic and sequestration crises, other major organ damage secondary to vasoocclusion, and occurrence of unrelenting priapism |
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benefits of exchange transfusion in SCD
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not raising total hemoglobin, and thereby total viscosity, while decreasing the percent of Hb SS cells. It also does not result in iron overload.
mostly done in neonates - umbilical access |
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lactate dehydrogenase
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surrogate marker for hemolysis in sickle cell disease
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beta thalassemia
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excess alpha chains cause damage to the red cell precursors and red cells and lead to profound anemia
expansion of the ineffective marrow =severe effects on development, bone formation, and growth major cause of morbidity and mortality is the effect of iron deposition in the endocrine organs, liver, and heart = from ^ intestinal absorption and effects of blood transfusion |
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alpha-thalassemias
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excess beta chains form 4 molecules, or hemoglobin H, which is soluble and does not precipitate in the marrow
unstable and precipitates in older red cells. Hence, the anemia of a-thal is hemolytic rather than dyserythropoietic 4 clinical presentations depending on how many genes of 4 total lost |
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major components of anemia of beta-thal
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**1) ineffective erythropoiesis with intramedullary destruction of a variable proportion of the developing red cell precursors
2) hemolysis resulting from destruction of mature red cells containing alpha-chain inclusions 3) hypochromic and microcytic red cells that result from the overall reduction in hemoglobin synthesis |
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major cause anemia in alpha-thal
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hemolysis (of older cells)
poorly hemoglobinized cells less effective erythropoiesis |
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clinical forms beta-thal
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1) silent carrier state
2) beta-thal trait (1&2 generally asympt, inheritance of one mutant gene) 3) thalassemia intermedia 4) thalassemia major (3&4 require medical management, homozygosity) |
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diagnostic features of homozygous beta-thal
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early onset of anemia,
characteristic blood changes, and elevated fetal hemoglobin concentrations found in no other condition confirm with demonstration of b-thal trait in both parents |
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diagnostic features of beta-thal trait
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mild anemia,
reduced mean cell volumes and mean cell hemoglobin concentrations elevated concentrations of the normal minor adult component of hemoglobin A2 (usually exceeding 3.5 percent) |
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thalassemia major vs intermedia
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major: come to medical attention in 1st year of life, subsequently require regular transfusions to survive
intermedia: present later or seldom need transfusions don't transfuse before 9.5g/dL Hgb reached in order to ensure need transfusion (not intermedia) |
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possible complications with age in even minor forms of beta-thal
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osteopenia (bone marrow density lower than norm)
iron loading in tissues ectopic marrow expansion |
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Hgb S and Beta-thal inheritence:
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Hgb S with Beta0-thal or severe beta+, resulting clinical disorder will be indistinguishable from SCD
HgbS with mild beta+ thal = milder sickling disorder |
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factors affecting severity of disease in beta-thal
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hetero vs homozygous
co-inheritance with HgbS or E number of aquired or environmental factors: - progressive splenomegaly - exposure to infections - SES factors - availability of medical care |
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beta-thal disease complications
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** iron overload! - major focus of management
w/o transfusions, ^2-5g/yr iron load on body; regular transfusions may double rate serum Fe more than normal once transferrin capacity exceeded, overwhelms body's capacity to deal with free radicals = oxidative damage - progressive dysfunction heart, liver, endocrine glands - disturbed sexual maturation from pituitary gland Fe, 2* amenorrhea, DM in 5% (hyperinsulinemia from poor liver fn), decreased bone density, osteopenia |
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iron-loading in heart
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myocytes increase transport of non-transferrin-bound iron = aggravating cardiac iron loading
= cardiac hypertrophy and dilation = degeneration of myocardial fibers = sometimes fibrosis ** survival of pts w beta-thal determined by magnitude iron loading in heart! can test w stress test and EKG echo to see if affecting heart |
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iron-induced liver disease
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common cause of death in older beta-thal patients
often complicated by infection with Hep C w/o chelating therapy, may get cirrhosis in first decade of life! |
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screening for beta-thal carriers
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most efficient = measurement of red cell indexes
estimation of Hgb A2 concentrations (in ppl with reduced MCV and MCHC) |
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prenatal diagonsis beta-thal
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fetal-blood sampling and assessment of globin chain synthesis
direct analysis of fetal DNA via chorionic-villus sampling |
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medical therapy for beta-thal
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transfusion - decision based on severity, failure to grow/develop, anemia
- goals include correction of anemia, suppression of erythropoiesis, and inhibition of increased gastrointestinal absorption of iron ** Hgb before transfusion <9.5g/dL (less iron accum) iron-chelating therapy: parenteral defefoxamine - prevents early death from cardiac disease - arrests progression liver fibrosis to cirrhosis bone marrow transplant |
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deferoxamine
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parenteral iron-chelating therapy
ideally maintain body iron below hepatic levels of <15mg/g dry weight balance bw effectiveness and toxicity by regular determination body iron burden (serrum ferritin levels measured, but hepatic iron is better correlated = liver biopsy) chelates iron in a one-to-one ratio removes somewhere between 30 and 70 mg of iron per day |
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clinical classifications of alpha-thals
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1) silent carrier state: hematologically normal
2) mild: microcytic, mild anemia, usually asympt (often mistaken for Fe-deficiency, but Fe doesnt help) 3) Hgb H disease: severe anemia, small misshapen RBC, splenomegaly, bone abnormalities; small and malnourished looking (E into RBC production) 4) Hydrops fetalis: loss of all 4 alpha genes, severe anemia and death before birth typical |
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splenectomy in beta-thal
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- spleen plays a role in clearing damaged RBC from the blood stream
- since all RBC in patients with severe thalassemia have some degree of damage, clearance by the spleen accelerates the rate of cell loss - in some patients, removal of spleen slows the rate of destruction just enough, that they can manage without transfusion, and still not have the unacceptable side-effects also get "work hypertrophy" and plasma volume increase, both worsening anemia |
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Chelators
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small molecules that bind very tightly to metal ions
eg EDTA (used to tx life threatening hypercalcemia), transferrin metal ion bound to the chelator is chemically inert |
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transfusion siderosis
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Metabolic disease
Iron accumulation due to multiple transfusions for intractable anemia linked to thalassemia, BM failure, aggressive CA treatment, often with cardiomyopathy Management Chelation with deferoxamine |
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symptoms beta-thal in infancy
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Anemia usually develops during the first few months of life and becomes progressively more severe.
The infants fail to thrive and may have: feeding problems, bouts of fever, diarrhea, and other gastrointestinal symptoms. earlier presentation = major; tranfusion dependency more likely |
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Cooley anemia
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inadequately transfused child w severe b-thal
Growth is stunted. With bossing of the skull and overgrowth of the maxillary region, can compress trigeminal nerve and inferior orbital N = chronic pain syndromes diploe widens; "hair on end" or "sun ray" appearance and a lacy trabeculation of the long bones and phalanges. Gross skeletal deformities can occur. liver and spleen enlarged, pigmentation of skin increases. - hypermetabolic state, (fever, wasting, and hyperuricemia) |
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indication of iron loading
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first: absence of the pubertal growth spurt and failure of the menarche
succeeding years, a variety of endocrine disturbances may develop: DM, hypogonadotrophic hypogonadism, growth hormone deficiency end of the second decade, cardiac complications arise, and death usually occurs in the second or third decade as a result of cardiac siderosis (acute cardiac death with arrhythmia, or intractable cardiac failure - precipitated by infection) |
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lab features of beta-thal major
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Hgb 4-6 g/dL
RBC: - anisopoikiolocytosis - hypochromia - target cell - basophilic stippling**** moderately elevated reticks nucleated RBCs Hb electrophoresis: HbA: 0-10% (norm >95%) HbF: 90-100% |
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life span sickle cell
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4-20 days (compared to 120)
engulfed by macrophages spleen - hypertrophy |
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haptoglobin
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binds free Hb in blood; inhibits oxidative activity
- haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system (mostly the spleen) measured to determine presence of intravascular hemolytic anenmia (extravascular hemolytic anemia, in spleen or liver, won't have release Hb into blood) - decline in Hp levels also positive acute phase protein |
