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192 Cards in this Set
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define anemia
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- decrease in whole body red cell mass
- precludes relative decreases in RBC count, hemoglobin, or hematocrit <- occur when plasma volume decreases |
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is anemia of pregancy true anemia?
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- no. just a reflection of increased plasma volume
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what is a practical working definition of anemia?
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- decrease in RBC, Hb, or hematocrit
|
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what causes anemia?
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1. decreased RBC production from:
- hematopoeitic cell damage - deficiency of factors for heme or DNA synthesis 2. increased RBC loss: - external blood loss - RBC destruction |
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what can cause hematopoietic cell damage?
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- infection
- drugs - radiation |
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what is necessary for heme synthesis?
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- iron
|
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what is necessary for DNA synthesis?
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- vit B12/ folate
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what is hemolytic anemia?
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RBC destruction
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acute posthemorrhagic anemia
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- first few hours, prior to hemodilution, there may be no decrease in Hb, hematocrit, and RBC count b/c of parallel loss of both RBCs and plasma
- marked reactive increase in platelets |
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what are the clincical findings in posthemorrhagic anemia?
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- similar to hypovolemia
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what is hemodilution?
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- a compensatory increase in plasma volume
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what causes iron deficiency anemia?
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- chronic blood loss
- dietary deficiency - increased iron requirement |
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what can cause chronic blood loss?
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- GI bleeds or menorrhagia
- major cause of iron deficiency in adults |
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define menorrhagia
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Excessive bleeding during menstruation.
|
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what can cause GI bleeds?
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- carcinoma of the colon
- hookworm disease in less developed countries |
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iron deficiency anemia
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- impaired heme synthesis
- you see hypochomia and microcytosis; decreased serum Fe and increased total Fe-binding capacity; decreased serum ferritin |
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what are the major etiologic factors of iron deficiency anemia?
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- dietary deficiency in infants and preadolescents
- excess menstrual bleeding - chronic GI blood loss |
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pernicious anemia
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- autoimmune gastritis -> lack of intrinsic factor and failure of B12 absorption -> delayed DNA replication
|
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what are the diagnostic features of pernicious anemia?
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- pancytopenia, oval macrocytes, and hypersegmented neutrophils; megalobalstic hyperplasia; acholorhydria; anti-intrinsic factor antiboides; hyperreflexia, absent position and vibration sense; impaired vit B12 absorption
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define acholorhydria
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no stomach acid; condition may be physiological or pharmacological (eg, omeprazole (Prilosec (R) ) or other antisecretory proton-pump blocking drugs prescribed commonly for gastric ulcers)
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what is the Schilling test?
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The Schilling test is a medical investigation used in patients with vitamin B12 deficiency. The purpose of the test is to determine if the patient has pernicious anemia.
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what are the major etiologic factors of pernicious anemia?
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- autoimmunity
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folate deficiency anemia
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delayed DNA replication
- pancytopenia, oval macrocytes, and hypersegmented neutrophils; megaloblastic hyperplasia |
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what are the major etiologic factors of folate deficiency anemia?
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- dietary deficiency
- malabsorption syndromes |
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aplastic anemia
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- generally diminished hematopoiesis
- pancytopenia, reticulocytopenia, marked hypocellualrity of bone marrow |
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what are the major etiologic factos of aplastic anemia?
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- toxic drugs and chemicals
- often idiopathic |
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anemia of chronic disease
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- most often normochormic and normocytic or macrocytic; maybe hypochormic and microcytic with decreased serum iron and decreased serum-iron binding capacity
|
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what are the major etiologic factors of anemia of chronic disease?
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- various chronic diseases (RA, renal disease, chronic infection
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myelophthisic anemia
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- bone marrow replacement, usually by malignant tumor
- severe anemia; small numbers of nucleated RBCs and immature granulocytes in the peripheral blood; tumors in the bone marrow |
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define: pancytopenia
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an abnormal deficiency in all blood cells (red blood cells and white blood cells and platelets); usually associated with bone marrow tumor or with aplastic anemia
|
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define macrocyte
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Macrocytes (larger than normal RBCs) are present.
|
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how does dietary deficiency cause anemia?
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- rare, except in infants
- human milk is low in iron -> infant iron storage is delepted by 6 months unless there is dietary supplementation - a risk in premies - a risk in elderly |
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increased iron requirement during pregnancy
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- fetus can deplete maternal iron stores
- can also occur in infants and preadolescents that outgrow borderline iron stores |
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what are the clincial manifestations of anemia?
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- pallor, fatique, dyspnea on exertion
- sometimes may have angina pectoris in people with coronary artery narorrowing from atherosclerotic disease |
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what happens during extreme anemia?
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- glossitis
- gastritis - koilonychia - Plummer-Vinson syndrome |
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define koilnychia
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Koilonychia means literally "spoon nails." It refers to nails (usually of the hand) which have lost their convexity, becoming flat or even concave in shape. In a sense, koilonychia refers to the opposite nail shape abnormality described as nail clubbing.
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define glossitis
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Glossitis is inflammation or infection of the tongue. It causes the tongue to swell and change color. Papillae may be lost, causing the tongue to appear smooth.
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Plummer-Vinson sydrome
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aka Paterson-Kelly syndrome or sideropenic dysphagia
- linked to severe, long-term iron deficiency anemia, which causes dysphagia due to esophageal webs. The cause of Plummer-Vinson syndrome is unknown; however, genetic factors and nutritional deficiencies may play a role. Women are at higher risk than men, particularly in middle age. - squamous cell carcinoma risk is increased. |
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what are the lab findings in anemia?
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- decreased Hb, hemocrit, and RBC count
- hypochromic microcytic erhthrocytes on peripheral smear - decreased [Fe] and increased total iron binding capacity (TIBC) - decreased in body stores |
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how do you measure body stores of Fe?
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- look at bone marrow for stainable hemosiderin or for serum ferritin
|
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what is the DDX for anemia like syndromes?
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- iron deficiency anemia: hypochoromic microcytic anemia (e.g. anemia of chronic disease or b-thalassemia minor)
- anemia of chornic disease: serum Fe is low, but TIBC is also low - b-thal: A2 Hb is increased |
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define megaloblastic anemias
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large, abnormal looking erythroid precursor cells (megaloblasts) in the bone marrow
|
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what causes megaloblastic anemias?
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- vit B12 or folate deficiency -> decreased DNA synthesis -> delay in nuclear division
- unimpeded cytoplasmic maturation |
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how do megaloblastic anemias appear morphologically?
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- nuclear-cytoplasmic asynchrony of large erythroid precursor cells with open, loose-appearing chromatin
|
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what happens when you have megaloblastic anemia?
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- impaired RBC production
- RBC destriction also in the bone marrow prior to release of mature RBCs into the peripheral blood |
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what is 'ineffective erythropoiesis'?
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- RBC destriction in the bone marrow prior to release of mature RBCs into the peripheral blood
|
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what lab abnormalities do you see with megaloblastic anemia?
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1. peripheral blood:
- pancytopenia - oval macrocytosis - hypersegmented neutrophils 2. bone marrow: - megaloblastic hyperplasia |
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describe the oval macrocytosis you see in megaloblastic anemia
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- mean corpuscular volume (MCV) > 110 fl (normally, about 87 fl)
|
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what do lab folate levels have to do with megaloblastic anemia?
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- further define the specific type of megaloblastic anemia
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list the different types of megaloblastic anemia
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1. vit B12 deficiency
2. Folate deficiency |
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what are the different types of vit B12 deficiency megaloblastic anemia?
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1. pernicious anemia
2. other forms: - total gastric resection - disorders of distal ileum - vegetarian diet - blind loop syndrome - broad spectrum antibiotic therapy - diphyllobothrium latum |
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pernicious anemia
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- most common form of vit B12 deficiency meg. an.
- autoimmune disorder -> autoimmune gastritis -> no intrinsic factor production -> no vit B12 absorption |
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what is often seen associated with pernicious anemia?
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- other autoimmune diseases (e.g. thyroid disease)
|
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what was autoimmune gastritis previously referred to as?
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- fundal or type A gastritis
|
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what is chronic autoimmune gastritis associated with?
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- achlorhydria
- anti-intrinsic factor and antiparietal cell antibodies - increased incidence of gastric carcinoma |
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what are clinical findings associated with pernicious anemia?
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- insidious onset with extreme RBC reduction
- lemon-yellow skin color - stomatitis and glossitis - subacute combined degeneration of the spinal cord |
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describe the insidious onset of pernicious anemia in elderly persons
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- preceded by lengthy subclincial period, where clinical manifestations are minimal
|
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describe the morphologic changes in subacute combined degeneration of the spinal cord in pernicious anemia
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- combined systems disease and posterolateral degeneration
- demyelination of posterior and lateral columns |
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describe the clinical symptoms in subacute combined degeneration of the spinal cord in pernicious anemia
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- ataxic gait
- hyperreflexia with extensor plantar reflexes - impaired position and vibratory sense |
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what is different neurologically between patients with folate vs. vit B12 deficiency?
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- vit B12: associated neuro abnormalities
- folate def: no neruo abnormalities |
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what are the lab findings associated with pernicious anemia?
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- pancytopenia, hypersegmented neutrophils, and megaloblastic hyperplasia of bone marrow
- anti-intrinsic factor antibodies - abnormal schilling test |
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how do you differentiate pernicious anemia from other types of megaloblastic anemias?
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- anti-intrinsic factor is seen in pernicious anemia, but not in other conditions.
- you may, however, see antiparietal cell antibodies in other conditions, but most frequently in pernicious anemia |
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what is the Schilling test?
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- abnormal results: impaired absorption fo vit B12 correctable by intrinsic factor
|
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what happens when you can't correct impaired absorption of vit B12 by using intrinsic factor?
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- intestinal malabsorption caused by crohn's disease, blind-loop syndrome, and giant tapeworm infestation
|
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what may absolute vegetarians have?
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- normal absorption by decreased vit B12 due to dietary deprivation
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total gastric resection and vit B12 deficiency
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- intrinsic factor is produced in the gastric fundus
- clinical picture is same as that for pernicious anemia |
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disorders of the distal ileum and vit B12 deficiency
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intrinsic factor- vit B12 complex is absorbed int he distal ileum
|
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strict vegetarian diet and vit B12 deficiency
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vit B12 is only found in foods of animal origin
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blind-loop syndrome and vit B12 deficiency`
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- bacterial overgrowth in a surgically induced intestinal blind loop results in depletion of vit B12
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broad spectrum antibiotic therapy and vit B12 deficiency
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- can result in bacterial overgrowth and vit B12 depletion
|
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diphyllobothrium latum infestation and vit B12 deficiency
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- the giant tapeworm of man, acuqired by ingestion of freshwarter fish, inhabits the intestines
-> vit B12 depletion |
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folate deficiency
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- no neurologic abnormalities (contrasted with vit B12 deficiency)
|
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how can you get folate deficiency megaloblastic anemia?
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- severe dietary deprivation
- pregnancy - Dilantin (phenytoin) - folic acid antagonist chemo - relative folate deficiency - intestinal malaborption |
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how does severe dietary deprivation cause folate deficiency?
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- most often seen in alcoholics and fad dieters
|
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how does pregnancy cause folate deficiency?
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- additonal demands of the fetus
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how does dilantin (phenytoin) therapy cause folate deficiency?
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- interferes with absorption of folate, or OCPs
|
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relative folate deficiency
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increased demand of folate bc of compensatory accelerated erythropoiesis in hemolytic anemia
|
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what is intestinal malabsorption caused by?
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- sprue
- Giardia lamblia |
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what is the prevalence of anemia of chronic disease?
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- second most common form, after iron deficiency anemia
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for which diseases does anemia of chronic disease secondarily occur?
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- RA
- renal disease - chronic infection |
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define: normochromic anemia
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anemia in which the hemoglobin content of the red cells as measured by the MCHC is in the normal range.
|
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define: normocytic anemia
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- marked by a proportionate decrease in the hemoglobin content, the packed red cell volume, and the number of erythrocytes per cubic millimeter of blood.
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how would you characterize anemia of chronic disease? it's normo___ and normo ____.
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- normochronic and normocytic
- may be moderately macrocytic when associated with renal disease |
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what serum markers may accompany anemia of chronic disease when associated with chronic inflammatory states (e.g. RA)
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- accompanied by decreased serum iron
- hypochromia - microcytosis - symptoms look like iron deficiency anemia |
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how do you differentiate anemia of chronic diesease from iron deficiency anemia?
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- TIBC ( Total iron binding capacity) is decreased in anemia of chronic disease
|
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what are the general characteristics of aplastic anemia?
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- markedly hypocellular bone marrow with almost total loss of hematopoietic cells:
- eryhroid and myeloid precursor cells - megakaryocytes - peripheral pancytnemia - reticulocytopenia |
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what is peripheral pancytopenia?
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- anemia
- leukopenia - thrombocytopenia |
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aplastic anemia is most often secondary to what?
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- toxic exposure
|
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what autoimmune condition can cause aplastic anemia?-
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- autoimmune dysfunction of cytotoxic T cells
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what are some other etiologic agents that can cause aplastic anemia?
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- radiation exposure
- chemicals (e.g. benzene and other organic compounds) - therapeutic drugs - viral infection |
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which drugs can cause aplastic anemia?
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- chloramphenicol
- sulfonamides - gold salts - chlorpromazine - anti-inflammatory and antimalarial drugs - alkylating agents used in cancer treatmetn |
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what is chlorampenicol?
|
a bacteriostatic antibiotic originally derived from the bacterium Streptomyces venezuelae, isolated by David Gottlieb.
- In the West, the main use of chloramphenicol is in eye drops or ointment for bacterial conjunctivitis. |
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which viruses can cause aplastic anemia?
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- human parvovirus
- hep C virus |
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what is myelophthisic anemia? what is it most commonly caused by?
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- form of bone marrow failure that is caused by replacement of the bone, most often by malignant neoplasm
|
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what is a less common cause of myelophthisic anemia?
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- bone marrow destruction from marrow fibrosis
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what may make you suspicious of myelophthisic anemia?
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- leukoerythroblastosis- a small number of nucleated RBCs and immature granulocytic precursors are seen in the peripheral blood smear
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broadly define hemolytic anemias
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- anemias resulting from increased RBC destruction
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list the hemolytic anemias
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1. warm antibody autoimmune hemolytic anemia
2. hemolytic isease of the newborn 3. hereditary spherocytosis 4. G6PD deficiency 5. Sickle cell anemia 6. b-thalassemia major 7. a-thalassemias |
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what do you seen when you have increased RBC destruction- the liberation of Hb and its degredation products?
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- increased unconjugated bilirubin
- increased urine urobilinogen - Hemoglobinemia and hemoglobinuria - disappearance of serum haptoglobins |
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what can increased unconjugated (indirect reacting) bilirubin result in?
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- acholuric jaundice: jaundice not accompanied by bilirubinuria (not liver disease)
- can eventually lead to pigment containing gallstones |
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define bilirubinuria
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the presence of bilirubin in the urine; often a symptom of liver disease
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what is a late complication of hyperbilirubinemia?
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- pigment containing gallstones, as a late complication
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define hyperbilirubinemia
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abnormally high amounts of bile pigment (bilirubin) in the blood
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what happens when you get very rapid RBC destruction within the circulation (intravascular hemolysis)?
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- hemoglobinemia
- hemoglobinuria - methemalbuminemia - hemosiderinuria |
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what is methemoglobin?
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a form of the oxygen-carrying protein hemoglobin, in which the iron in the heme group is in the Fe3+ state, not the Fe2+ of normal hemoglobin. Methemoglobin is unable to carry oxygen. It is blue in color. The NADH-dependent enzyme methemoglobin reductase (AKA diaphorase I) is responsible for converting methemoglobin back to hemoglobin.
|
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what are haptoglobins?
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- protein in the blood plasma that binds free Hb released from RBCs, and thereby inhibits its oxidative activity.
- the haptoglobin-hb complex will then be removed by the reticuloendothelial system (mostly the spleen) - In clinical settings, the Haptoglobin assay is used to screen for hemolytic anemia |
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when will you finally be able to see elevation of serum Hb after intravascualr hemolysis (e.g hemolytic transfusion reactions)
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- only after the serum haptoglobins are used up and not detectable
|
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what else, besides increased red cell destruction, do you see in hemolytic anemias?
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- increased erythropoiesis: compensates for shortened RBC survival
1. normoblastic erythroid hyperplasia in bone 2. reticulocytosis 3. polychromatophilia |
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how do you realize that your patient has reticulocytosis?
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- increased number of circulating reticulocytes can be identified by residual stainable RNA
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why do you get a moderate increase in MCV in hemolytic anemia?
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- reticulocytes are slighlyt larger than other RBCs
- MCV can be increasd to ~105fl |
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how do you detect polychromatophilia?
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- increased number of slightly larger BRCs that stain with a bluish cast, roughly equivalent to increased reticulocyte count
|
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define: polychromatophilia
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- aka polychromasia
1. the property of being stainable with various stains; 2. a condition in which the erythrocytes, on staining, show various shades of blue combined with tinges of pink |
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what is intracorpuscular hemolytic anemia?
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- defects are often genetically determined
- in the RBC itself |
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what is extracorpuscular hemolytic anemia?
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- defects are aquired from irculating antibodies or an enlarged spleen
|
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how do immune hemolytia anemias present? list the four types
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- recent onset
1. warm antibody autoimmune hemolytica anemia 2. cold agglutinin disease 3. chronic cold agglutinin disease 4. hemolytic disease of the newborn |
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what is the prevalence of warm antibody autoimmune hemolytic anemia?
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- most common form of immune hemolytic anemia
- usually secondary to SLE, Hodgkin disease, or non-Hodgkin lymphomas |
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what causes warm antibody autoimmune hemolytic anemia?
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- iGG autoantibodies react with cell surface antigens
- these antibodies are active at 37 degrees |
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what are the general clincial characteristics of immune hemolytic anemias?
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- general features of hemolytica anemia
- spherocytosis - postiive direct COombs test |
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why do you get spherocytosis in immune hemolytic anemias?
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- you get loss of membrane protein by serial passage of antibody coated RBCs through the spleen
|
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what is a Direct Coombs test?
|
The direct Coombs tes is used to detect if antibodies or complement system factors have bound to RBC surface antigens in vivo.
- used clinically when immune-mediated haemolytic anaemia is suspected. - A positive Coombs test indicates that an immune mechanism is attacking the patient's own RBC's. This mechanism could be autoimmunity, alloimmunity or a drug-induced immune-mediated mechanism. |
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what is an indirect Coombs test?
|
The indirect Coombs test is used to detect in-vitro antibody-antigen reactions.
- In antenatal care, the IAT is used to screen pregnant women for antibodies that may cause hemolytic disease of the newborn. |
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what causes cold agglutinin disease?
|
- IgM antibodies optimally active at temperatures below 30
- usually, the antibodies target the I blood group antigen Notes: All individuals have circulating antibodies directed against red blood cells, but their concentrations are often too low to trigger disease (titers under 1:64 at 4°C). In individuals with cold agglutinin disease, these antibodies are in much higher concentrations (titers over 1:1000 at 4°C). |
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what is clod agglutinin disease often complicated by?
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- mononucleosis infection
- mycoplama pneumoniae infection (can help facilitate the diagnosis by demonstrating cold agglutinins) |
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what is chronic cold agglutinin disease often associated with?
|
- lymphoid neoplasms
- mediated by anti-i antibodies - Raynaud phenomenon |
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who is chronic cold agglutinin disease clincially characterized?
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- agglutination and hemolysis in tissue sites exposed to the cold
- associated with Reynaud phenomenon - worse in cold weather - some episodes of jaundice - sometimes hemoglobinemia and hemoglobinuria |
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what causes hemolytic disease of the newborn (aka erythroblastosis fetalis)?
|
- maternal antibodies cross the placenta and react with fetal
RBCs -> fetal hemolytic anemia 1. maternal alloimmunization ot fetal RBC antigens (D antigen of the Rb blood groups system) 2. ABO incompatibility |
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what is the mom's blood type for the most frequently occurring form of Rh-mediated hemolytic disease of the newborn?
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- mom: d
- fetus: D |
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what permutations of blood groups can you have for ABO incompatibility?
|
1. mother is O and child is A, or B
2. mother is A, child B or AB 3. mother is B, child A or AB |
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what does hemolytic disease of the newborn cause?
|
1. kernicterus: stainign of the basal ganglia and other CNS structures by unconjugated bilirubin -> neurologic damange
2. stillbirth 3. hydrops fetalis |
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define hydrops fetalis
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- gross edema of the entire body wih severe anemia occurring in the hemolytic diseaseas in the newborn.
- can cause heart failure with massive generalized edema |
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how can you prevent hemolytic disease of the newborn?
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- by administration of anti-D IgG antiserum to D-negative mothers at the time of delivery (or at time of terminatioN) prevents maternal alloimmunization
|
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what is paroxysmal nocturnal hemoglobinuria?
|
- uncommon acquired intracorpuscular defect
- increases sensitivity to complement-induced RBC lysis -> intravascular hemolytic anemia, pancytopenia, and increase incidnece of venous thrombosis |
|
what do you see when you get up in the mornings if you have paroxysmal nocturnal hemoglobinuria?
|
- hemoglobin containing urine in the first pee of the morning
|
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define: paroxysmal
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recurring "sudden attacks" of symptoms.
|
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tell me about the molecular cause of paroxysmal nocturnal hemoglobinuria
|
- somatic mutation of PIG-A
- causes impaired synthesis of the GPI anchor needed to tie proteins to cellular surfaces (CD 55, CD59, C8) - these proteins protect RBCs, granulocytes, and platelets from complement mediated lysis |
|
which proteins protect RBCs, granulocytes, and platelets from complement mediated lysis?
|
- CD55
- CD59 - C8 - attached to the cellular surface by GPI |
|
how do you diagnose paroxysmal nocturnal hemoglobinuria?
|
- use flow cytometry to show a poluation of CD59- negative erythrocytes
- used to be diagnosed by the Ham test for in vitro completment induced hemolysis of acidified serum |
|
mwahahaha.. in which disease do you find the key words 'PIG' and 'HAM'?
|
- paroxysmal nocturnal hemoglobinuria
|
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list the hemolytic anemias caused by membrane slektal protein abnormalities
|
1. hereditary spherocytosis
2. hereditayr elliptocytosis (ovalocytosis) |
|
epidemiology of hereditary spherocytosis
|
- autosomal dominant hemolytic anemia
- most common intracorpuscular inherited hemolytic anemia observed in whites |
|
what characterizes hereditary spherocytosis?
|
- spherocytes selectively trapped in the spleen -> splenomegaly
- increase in erythrocyte osmotic fragility to hypotonic saline - increase in mean corpuscular hemoglobin concentration (MCHC) |
|
what do you see in spherocytosis that you don't usually see in other forms of anemia?
|
- increase in the MCHC
|
|
what genes cause hereditary spherocytosis?
|
- variety of molecaulr defects in the genes encoding:
- spectrin - ankyrin - protien 4.1 - other erythrocyte membrane skeletal proteins -> deficinecy in SPECTRIN |
|
what is spectrin?
|
- Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane of many cell types in pentagonal or hexagonal arrangements
- cleavage causes the membrane to form blebs and ultimately to be degraded - Association with the intracellular face of the plasma membrane is by indirect interaction, through direct interactions with protein 4.1 and ankyrin, with transmembrane proteins. |
|
what is hereditary elliptocytosis (ovalocytosis)?
|
- autosomal dominant disorder characterized by elongated, oval red cells
- may be marked by hemolytic anemia and splenomegaly - often does not cause anemia |
|
which is the most common form of enzyme deficiency hemolytic anemia?
|
- G6PD deficiency
|
|
describe the genetics behind G6PD deficiency
|
- X-linked
- occurs in 10% of African americans and in mediterranians - G6PD is an enzyme in the PPP pathway; it serves to maintain levels of NADPH - NADPH is needed to maintain levels of glutathione and protect cells from oxidative stress |
|
what do you see in G6PD deficiency? what causes these symptoms?
|
- hemoglobinemia
- hemoglobinuria - caused by oxidative stress brought on by infection and drugs |
|
which drugs can cause increase levels of oxidative stress and cause hemolytic anemia in G6PD deficiency?
|
- primaquine (antimalarial)
- sulfonamides - fava beans |
|
what do you see in the peripheral blood smear in a patient with G6PD deficiency?
|
- bites cells (RBCs that look like they have a bite taken out of them)
|
|
list the two types of enzyem deficinecy hemolytic anemias
|
1. G6PD deficiency
2. pyruvate kinase deficiency |
|
pyruvate kinase deficiency
|
- second most common enzyme deficinecy hemolytic anemia
- autosomal recessive disorder characterized by hereditary nonspherocytic hemolytic anemia |
|
what is one way to differentiate G6PD deficiency from pyruvate kinase deficiency?
|
- G6PD is self-limited
- PK deficiency is chronic and sustained |
|
list the hemoglobinopathies
|
1. hemoglobin S disorder
2. hemoglobin C disorder 3. hemoglobin E disorder |
|
what is the general characteristic of hemoglobinopathies?
|
- genetically determined abnormalities of hemoglobin strucutre
- S is most common - C less common - E is found in some urban centers |
|
describe the epidemiology of hemoglobin S disorders
|
- 7% of african americans carry the Hb S gene
- in africa, some parts have more than 1/3 affected - may be connected to falciparum malarial resistance |
|
what is seen in persons of african origin that may protect against malaria?
|
- erythrocyte G6PD deficiency
- absence of Duffy blood group antigens (Duff Fy a- b-) |
|
where is the mutation for hemoglobin S?
|
- point mutation in codon 6 of the b-globin gene; valine -> glutamic acid -> abolishes recognition site for restriction endonuclease Mst II
|
|
how do you perform prenatal diagnosis for hemoglobin S disorders?
|
- either a chorionic villus sample or amniotic sampling for the point mutation in codon 6 of the b-globin gene
|
|
what is abnormal about hemoglobin S?
|
- polymerizes at low oxygen tension -> form tactoids that distort RBC shape:
- sickle, elongated shapes - repeated sickling episodes stiffen the RBC membrnates -> more likely to hemolyse - also more likely to obstruct the microvasculature |
|
how do you test for hemoglobin S disorders?
|
- characterized by a positive sickle cell preparation (in vitro sickling of RBCs on exposure to reducing agents like sodium metabisulfite)
|
|
in which disorders is hemoglobin S present?
|
- sickle cell anemia
- sickle cell trait - sickle C disease - sickle cell thalassemia |
|
what causes sickle cell anemia?
|
- homozygous form of hemoglobin S
|
|
what do you see in sickle cell anemia?
|
1. severe hemolytic anemia
2. chronic leg ulcers 3 vaso-occlusive painful crises 4. infarctions in lungs and spleen 5. aplastic crises 6. infectious complications (Salmonella osteomyelitis) |
|
what are vaso-occlusive 'painful crises' seen in sickle cell disease?
|
- severe pain in the limbs, back, chest and abdomen
- often precipitated by infection or dehydration |
|
what happens with repeated lung and spleen infarcts in sickle cell disease?
|
- spleen becomes congested and enlarged in childhood
- with repeated infarcts, it gets smaller and fibroses (autosplenectomy) |
|
what are aplastic crises seen in sickle cell disease?
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- not the same as painful crises
- precipitous fall in Hb concentration - usually provoked by viral infection like human parvovirus |
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what causes sickle cell trait?
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- hemoglobin S in heterozygous form
- usually has no clincial consequences |
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in what population are hemoglobin C disorders mainly seen?
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- africans
- homozygous: mild hemolytic anemia with slenomegaly, target cells, and intraerythrocytic crystals - heterozygous: result in disease only when coinherited with other abnormal hemoglobins (e.g. Hb S) |
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in what population are hemoglobin E disorders mainly seen?
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- southeast asia
- have increased significantly in urban areas in recent years - clinical and lab findings are similar to Heme C disorders |
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what are thalassemias?
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- genetic disorder characterized by deficient production of a or b-globin chains of Hb.
- heme synthesis is NOT affected |
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what is the epidemiology of b-thalassemia?
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- most common form of thalassemia in the mediterranean and in the US
|
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what is the genetic defect in b-thalassemia?
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- defects in the promoter, intron, or coding sequence of b-globin gene
|
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what is b-thalassemia major?
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- aka Mediterranean anemia
- aka Cooley anemia - compound heterozygosity or homozygosit of the thalassemic variants of the B-globin gene |
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what is the clinical presentation of b-thalassemia major?
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1. marked anemia
2. splenomegaly 3. distortion of skull, facial bones, and long bones 4. thalassemic RBC morphology 5. increased Hb F 6. generalized hemosiderosis |
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what causes the marked anemia seen in b-thalassemia major?
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- decrease in Hb synthesis
- shortened RBC lifespan due to aggregation of insolube excess of a-chains - ineffective erythropoisis - relative folate deficiency |
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why do you get skull, facial bone and long bone distortion in b-thal major?
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- expansion of erythroid bone marrow
|
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what is thalassemic RBC morphology?
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- microcytosis
- hypochromia - target cells - changes in size and shape |
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what is Hb F?
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- fetal Hb (a2g2)
- increased throughout life in b-thal major patients |
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why do you get generalized hemosiderosis in b-thal major patients?
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- chronic hemolysis
- ineffective erythropoiesis - repeated transfusions |
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what causes b-thalassemia minor?
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- heterozygous inheritance of thalassemic variants of the b-globin gene
|
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what are the clincial manifestations of b-thal minor?
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- minimal hypochromic microcytic anemia
- INCREASE in Hb A2 (a2g2) |
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what is the normal fraction of Hb A2 in the blood?
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- very minor fraction
|
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what are the types of b-thalassemias?
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1. B-thal major
2. B-thal minor 3. sickle cell thal |
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what is sickle cell thal?
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- a type of b-thal
- results from coinheritance of Hb S gene and a tahlassemic ariant of the b-globin gene (compound heterozygosity) |
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what is the clinical presentation of sickle cell thal?
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- similar to, but often less severe than, sickle cell anemia
|
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what is the epidemiology of a-thalassemia?
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- most common form in SE Asia
|
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what is the genetic basis for a-thalassemia?
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- deletions of one or more of the four a-globin genes
- in normal people, there is a duplication of the a- globin gene, with a pair of identical a-globin genes on each member of chr. 16 |
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what are some variants of a-thal characterized by?
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- increased concentration of Hb Barts (g4) or Hb H (b4)
|
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hemolytic anemias due to mechanical disruption of circulating erythrocytes- what are they associated with?
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- aortic valve prostheses
- DIC - thrombotic thrombocytopenic purpura - microangiopathic hemolytic anemia |
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what is microangiopathic hemolytic anemia?
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- partial occlusion of small vessels that causes the mecahnical disruption of RBCs
|
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what do you see in the blood when you have hemolytic anemia due to mechanical disruption of circulating erythrocytes?
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- RBC fragements:
- schistocytes - helmet cells |