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Disorders of Hemoglobin (STRUCTURALLY ABNORMAL HEMOGLOBINS (SICKLE CELL…

- - - - Vasoocclusion--> protean manifestations
        Intermittent episodes in connective & musculoskeletal--> ischemia manifested by acute pain and tenderness, fever, tachycardia, and anxiety.
        These recurrent episodes: painful crises: most common clinical manifestation
        frequency, severity vary
        Pain can develop almost anywhere in body and may last from a few hrs to 2 w
        Repeated crises requiring hospitalization (>3 episodes/yr) correlate w/ reduced survival in adult life, (episodes a. w/ accumulation of chronic end-organ damage)
        Provocative factors: infection, fever, excessive exercise, anxiety, abrupt changes in temp, hypoxia, or hypertonic dyes.
      - Repeated microinfarction can destroy tissues having microvascular beds prone to sickling
        splenic function frequently lost within first 18–36 m of life--> susceptibility to infection, partic by pneumococci
        Acute venous obstruction of spleen (splenic sequestration crisis), rare occurrence in early childhood, may require emergency transfusion and/or splenectomy to prevent trapping of entire arterial output in obstructed spleen
        Occlusion of retinal vessels--> hemorrhage, neovascularization, eventual detachments
        Renal papillary necrosis--> isosthenuria
        More widespread renal necrosis--> renal failure in adults, a common late cause of death
        Bone and joint ischemia--> aseptic necrosis, esp of femoral or humeral heads; chronic arthropathy; unusual susceptibility to osteomyelitis (may be caused by organisms, such as Salmonella, rarely encountered in other settings); hand-foot syndrome caused by painful infarcts of digits and dactylitis
        Stroke esp common in children; a small subset tends to suffer repeated episodes; less common in adults & often hemorrhagic
        partic painful complication in males: priapism (bc infarction of penile venous outflow tracts); permanent impotence a frequent consequence
        Chronic lower leg ulcers probably arise from ischemia & superinfection in distal circulation
      - Granulocytosis common
        white count can fluctuate substantially and unpredictably during and between painful crises, infectious episodes, and other intercurrent illnesses
      - Acute chest syndrome:
        a distinctive manifestation charac by chest pain, tachypnea, fever, cough, arterial oxygen desaturation
        can mimic pneumonia, pulmonary emboli, bone marrow infarction and embolism, MI, or in situ lung infarction; Often difficult or impossible to distinguish
        thought to reflect in situ sickling within lung--> pain & temporary pulmonary dysfunction
        Pulmonary infarction & pneumonia: most frequent underlying or concomitant conditions in pxs w/ this syndrome
        Repeated episodes correlate w/ reduced survival
        Acutely, reduction in arterial oxygen saturation esp ominous bc promotes sickling on a massive scale
        Chronic acute or subacute pulmonary crises--> pulmonary HTN and cor pulmonale, an incr common cause of death as pxs survive longer
      - Most: hemolytic anemia (hematocrits from 15 to 30%, and significant reticulocytosis)
        Anemia once thought to exert protective effects against vasoocclusion (by decr viscosity) but now thought that incr in hematocrit & feedback inhibition of reticulocytosis beneficial, even at expense of incr blood viscosity (maybe bc of adhesive reticulocytes)
      - Chronic subacute CNS damage in absence of an overt stroke: common phenomenon beginning in early childhood
        circulatory dysfunction due to a likely CNS sickle vasculopathy; correlate w/ an array of cognitive and behavioral abnormalities in children and young adults
        important to be aware of these often subtle changes bc they can complicate clinical management or be misinterpreted as “difficult px” behaviors :((((((((((
      - remarkable clinical heterogeneity
        Some virtually asymptomatic into or even through adult life
        others suffer repeated crises requiring hospitalization from early childhood
        sickle thalassemia & sickle-HbE tend to have similar, slightly milder symptoms, perhaps bc of ameliorating effects of production of other Hbs within RBC
        Hb SC disease, one of more common variants of sickle cell anemia, frequently marked by lesser degrees of hemolytic anemia & a greater propensity for development of retinopathy and aseptic necrosis of bones; but mostly resemble sickle cell anemia
        Some rare Hb variants actually aggravate sickling phenomenon
      - clinical variability in different pxs inheriting same disease-causing mutation (sickle Hb)--> sickle cell disease focus of efforts to identify modifying genetic polymorphisms in other genes that might account for heterogeneity
        interesting patterns ex genes affecting
        infl response or cytokine expression appear to be modifying candidates
        transcriptional regulation of lymphocytes may also be involved