UNIT 4 CLS 292 ANEMIAS STUDY GUIDE

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what is anemia? (learning objective)

most common hematologic disorder and is a reduction below normal in hemoglobin, hematocrit, or red blood cell number that is normally found in individual according to age and sex or premature RBC destruction

anemia is a secondary condition

what are the general symptoms of anemia? (learning objective)

generally related to the underlying lack of O2-carrying capacity

• fatigue

• weakness

• dizziness

• tachycardia

• pallor of skin and mucous membranes

what specific symptom would a patient with hemolytic anemia have? (learning objective)

jaundiced (due to accumulation of bilirubin)

what specific symptoms would a patient with iron-deficiency anemia have? (learning objective)

• PICA

• smooth tongue

• spoon-shaped nails (koilonychia)

what specific symptom would a patient with megaloblastic anemia have? (learning objective)

big, beefy tongue

what are the effects of sudden anemia? (learning objective)

• tissue hypoxia → causes EPO to increase

• the bone marrow is stimulated for various reasons:

  • to increase stem cell activity → results in erythroid precursors

  • shortening of maturation time

  • premature release of retics → if the hypoxia is severe, it could release NRBCs

essentially the sudden effects of anemia causes an increased demand of RBCs which causes the normal maturation of RBCs will be disrupted

what is the BMs response in when there is sudden anemia?

• there will be a presence of “shift” retics or stress retics

  • retics will usually lose their RNA within 24 hours in the PB but in stress retics, it will take 2-2.5 days to lose their RNA

  • stress retics are released earlier from the BM and will have increased RNA

• increased RBC production (3-fold) in moderate anemia and (5-fold) in severe anemia

• bone marrow is hyperactive with increased proliferation → erythroid hyperplasia

what determines the maturation of reticulocytes?

hematocrit → the lower the hematocrit, it will move out of the BM earlier and mature in the reticulocytes for a longer time

what is iron deficiency anemia? (learning objective)

occurs when the body storage of iron have been depleted which can occur due to inadequate dietary iron uptake, inadequate iron absorption, and abnormal iron loss

what is the normal distribution of iron?

• 60-80% of iron is functional and serves in metabolic (hemoglobin/myoglobin) or enzymatic functions

• remainder of iron serves as a transport (uses transferrin to be transported) or storage forms (ferritin and hemosiderin → mostly in liver and bone marrow)

iron cannot exist alone and must be bound to a protein which is transferrin

how does iron get in and out of the body?

iron has a regulatory system which is controlled through the hormone, hepcidin→ iron will leave the body by being stored in the cells and getting sloughed off… when RBCs are degraded, macrophages will recycle them

what is the pathogenesis of iron-deficiency anemia? (learning objective)

blood loss (storage pool of RBCs is being depleted)

• GI bleed, heavy menstruation, injury or accident

really bad diet (rare)

• diet is multifaceted, meaning many things can be affecting diet

• iron may not be absorbed

treated with oral iron supplements if anemia is not due to GI bleed and always establish the cause of IDA first

what would the RBC morphology look like in those with iron-deficiency anemia? (learning objective)

cells are hypochromic and microcytic with increased anisocytosis and poikilocytosis (elliptocytes)… reticulocytes are decreased and platelets are increased

• anisocytosis is because each new wave of RBCs has less and less iron

• lack of iron is the cause of the decreased reticulocytes

• myeloid:erythroid ratio is decreased due to increased erythropoiesis

all RBC indices are decreased

what would the results of the iron studies look like in those with iron-deficiency anemia?

• decreased serum iron

• increased total iron binding capacity (TIBC)

  • TIBC → the total amount of Fe capable of being bound to transferrin

• decreased ferritin

  • ferritin → primary storage form of soluble iron; readily released for heme synthesis and consists of a spherical protein shell that can store up to 4500 iron atoms

  • ferritin without its shell = apoferritin

what is the first stage of iron deficiency anemia?

iron depletion

• iron stores are exhausted causing decreased ferritin

• there is no anemia yet and RBC morphology is normal

• RDW may be increased → could be the first hematologic indication of a developing iron deficiency anemia

what is the second stage of iron deficiency anemia?

iron deficient erythropoiesis

• anemia and hypochromia is not detectable

• RBCs may be slightly microcytic

• will have decreased transferrin saturation and increased erythrocyte protoporphyrin

what is the third stage of iron deficiency anemia?

iron deficiency anemia

• iron tests are markedly abnormal → severely deficient total body iron

• microcytic hypochromic RBCs

what are the general characteristics of anemia caused by abnormal iron metabolism?

• result of a block in the incorporation of iron into the protoporphyrin ring to form heme and defective iron utilization (usually due to the slow release iron from macrophages)

  • has a positive iron balance and could lead to an increase in iron stores (especially in spleen, liver, and BM) which results in increased serum ferritin levels

• results in a lack of iron for Hb synthesis and a blood picture that is similar to IDA

• iron is absorbed at normal rates but it is used at less than normal rates for erythropoiesis

what is sideroblastic anemia? (learning objective)

body has inefficient erythropoiesis due to a defective function of the HSC

• elevated body iron storage, serum iron and serum ferritin is increased

  • decreased TIBC

• low reticulocyte count and accumulation of iron in the mitochondria of the erythroid precursors

what would the PB look like in sideroblastic anemia? (learning objective)

• ringed sideroblasts → siderotic granules surround the nucleus of the NRBCs due to the defective Hb synthesis

• will have a dimorphic population of normochromic and hypochromic cells

  • MCV, MCH, and MCHC may be normal

  • RDW will be increased and has dual peaks on the histogram

• will have a dual population of macro and microcytes

  • mild macrocytes are found in sideroblastic anemia that is associated with alcoholism

• RBCs could have pappenheimer bodies

must use prussian blue to confirm sideroblastic anemia

what can cause sideroblastic anemia?

• can be sex-linked recessive gene (hereditary sideroblastic anemia)

• can be acquired and could be associated with other things like leukemia, drugs (can interfere with heme synthesis) and lead poisoning (basophilic stippling) (also benzenes)

  • more common

  • lead poisonings blocks enzymes in the heme biosynthetic pathway → can cause mental defects

    • would actually have siderocytes

usually moderate to severe anemia

what is the treatment for sideroblastic anemia?

pyridoxine therapy

• usually tried on those who have hereditary sideroblastic anemia

  • less than ½ experience a return to normal Hb levels

  • iron overload will decrease responsiveness which is treated through phlebotomy and chelation therapy

folic acid

• only given to those with megaloblastic features (seen in liver disease & alcoholism)

secondary hereditary anemia could be from a disease, toxin, or drug which is corrected through treatment of the primary disease or the elimination of toxin/drug

what are porphyrias?

a group of inherited disorders that are characterized by a block in porphyrin synthesis due to a defect in one or more enzymes in the pathway of heme synthesis → the heme precursors will accumulate in the tissues and large amounts are excreted in the urine (port wine) and/or feces

• common lab findings → photosensitivity, abdominal pain, neuropathy

what is congenital erythropoietic porphyria (CEP)?

a rare autosomal recessive disease where excess porphyrins are deposited in body tissues and excreted in urine and feces → presence of CEP can be verified by intense fluorescence with UV light

cause of hemolytic anemia that is with CEP is unknown

what would the RBC morphology look like in those with congenital erythropoietic porphyria (CEP)?

mild to severe normocytic anemia with anisocytosis and poikilocytosis and significant polychromatophilia (reticulocytes) and NRBCs

• RBCs will fluoresce with UV light

• BM will show erythroid hyperplasia (more cells) and a portion of the normoblasts will have intense fluorescence

• serum iron and storage is usually normal

• large amounts of uroporphyrin I and coproporphyrin are excreted in urine and feces

what is erythropoietic photoporphyria (EPP)?

an autosomal dominant trait that causes a overproduction of protoporphyrin-immediate precursor of heme → ends up building up in the cell and leaks into the skin (causes hypersensitivity to sun) dermal capillaries and can be found in the skin, liver, blood, and feces (will not be present in the urine because of its insolubility)

adequate amounts of heme are produced → no anemia is present

what are the laboratory findings of erythropoietic photoporphyria?

cytoplasm of normoblasts fluoresces intensely but blood and BM will usually have no abnormalities

• RBC’s plasma and feces contain large amounts of protoporphyrin which is not found in urine

what is the therapy for congenital erythropoietic porphyria?

quality of life is improved by minimizing the scarring and mutilation with effective dermatologic treatment so avoidance of sunlight is critical & blood transfusions with administration of chelators (to avoid iron overload)

• most usually do not survive beyond 50

• attempts to decrease excess porphyrins have been unsuccessful

what is the treatment for erythropoietic photoporphyria?

protect skin from sunlight (high does of B-carotene have been seen to improve tolerance to sunlight) and blood transfusions may be used to suppress erythropoiesis

• splenectomy could be helpful if hemolysis and splenomegaly are prominent

  • this is because spleen would want to cull the abnormal cells (driver)

  • IRON IS TRAPPED IN MACROPHAGES

how are macrocytic anemias characterized? (learning objective)

abnormally large RBCs (MCV >100 fL) with normal hemoglobin content (MCHC) and can have megaloblastic (vitamin B12 or folic acid deficiency) and non-megaloblastic anemia that are caused by different things

• non-megaloblastic anemia is usually a result of an acute blood loss resulting in a premature release of reticulocytes (shift retics)

  • associated with: alcoholism, hypothyroidism, liver disease, splenectomy, pregnancy

what is the pathogenesis of megaloblastic anemia? (learning objective)

vitamin B12 and/or folate deficiency (from bad diet, absorption problems, folate-antagonist drugs)

• deficiency makes it hard to make DNA but RNA production runs smoothly

  • nucleus which is full of DNA lags behind the cytoplasm which is full of RNA in development and the cell divides more slowly

• maturation is asynchronous (cytoplasm is mature but nucleus is immature) in the bone marrow

treatment depends on the cause of anemia

what would the RBC morphology look like in those with megaloblastic anemia? (learning objective)

red cells are macrocytic (would see great big oval macrocytes) with hypersegmented (>6) neutrophils → moderate-marked poik and aniso, NRBCs and inclusions like basophilic stippling and howell-jolly bodies

what is pernicious anemia? (learning objective)

a type of megaloblastic anemia that occurs when there is a vitamin b12 deficiency → gradually develops (sneaky) and has a defective cellular maturation due to impaired NA synthesis

• intrinsic factor (IF) vitamin b12 complex (NEED IF-VITAMIN B12 COMPLEX) binds to receptor sites on epithelial cells of the small intestine and is absorbed in which B12 is then transported by protein to liver, BM, and other sites of rapidly dividing cells

• in a lot of cases, vitamin b12 deficiency is secondary to a deficiency of intrinsic factor

what are the various clinical findings for pernicious anemia? (learning objective)

• typical anemic symptoms → fatigue, weakness, pale or yellowish skin (due to bilirubin build up), irregular heartbeats (can also hear their heartbeat), shortness of breath, dizziness or lightheadedness, chest pain, cold hands and feet

• smooth pale tongue or beefy red tongue

• loss of weight and appetite

• atrophy of gastric parietal cells

• neurologic disturbances → leads to megaloblastic madness

  • altered personality, dementia, spastic weakness and ataxia due to demyelination of lateral and posterior columns of spinal cord

what would the RBC morphology look like in those with pernicious anemia? (learning objective)

macrocytic and tend to be elongated (ovalocytes) with an increased MCH and normal or slightly decreased MCHC

• leukocyte and platelet development will be affected by being decreased

• in BM, nuclear/cytoplasmic asynchrony is present so the end product is macrocytes → may see giant bands, metamyelocytes, and hypersegmented neutrophils (specific for megaloblastic anemia)

• may see howell-jolly bodies and cabot rings

• moderate to severe aniso and poik (usually more severe when anemia is severe)

• polychromatophilia

what is used to determine the cause of pernicious anemia?

gastric analysis

• determines cause of pernicious anemia which is a decrease in acidic gastric material secretions

schilling test

• determines vitamin B12 malabsorption

• radioactive-labeled vitamin B12 is taken orally then a 12 hr urine specimen is collected → labeled vitamin B12 is measured

• about ~7.5% of the administered dose should be present in the urine specimen → if less, then the test is consistent with B12 deficiency

what is folic acid deficiency? (learning objective)

another type of megaloblastic anemia and is more common due to dietary deficiency and defective absorption with dietary deficiency being the most common (found in eggs, milk, fruit, and leafy vegetables)

• major role is in DNA synthesis

• body store in the liver is small and the minimum daily requirement is 50 micrograms → anemia will develop in 3-6 months in severe folate deficient diet

• malabsorption syndromes can be caused by different intestinal disorders

• certain types of anemias can involve rapid proliferation of HSC → can lead to folate deficiency

what is the therapy for megaloblastic anemia? (learning objective)

treat with specific deficient vitamin (anemia symptoms go away quickly after treatment) but will cause a rise in retics 4 days after therapy

• degree of retics are proportional to the severity of the anemia

• vitamin b12 therapy could reverse the peripheral neuropathy but spinal cord damage is irreversible

• pernicious anemia has to be treated with lifelong monthly parenteral doses of b12 because of the inability to absorb oral vitamin b12

what is nonmegaloblastic macrocytic anemia? (learning objective)

has 3 common causes → liver disease, alcoholism, and reticulocytosis

• macrocytes are not as pronounced and are usually round not oval

• hypersegmented neutrophils are not present

• leukocytes and platelets are normal

what is the most common disease associated with nonmegaloblastic macrocytic anemia?

liver disease → minor finding among the other abnormalities associated with liver disease

• RBC survival seems to be significantly decreased in: alcoholic liver disease, infectious hepatitis, biliary cirrhosis, obstructive jaundice, and unknown reason (idiopathic)

• anemia is usually mild → average Hb is 12 g/dL with normocytic, macrocytic or microcytic (may have a high RDW) and thrombocytopenia

how is alcoholism associated with nonmegaloblastic macrocytic anemia?

macrocytosis is probably the result of folate deficiency due to decreased dietary intake but alcohol seems to also interfere with folate metabolism and also with:

• reticulocytosis is associated with hemolysis and GI bleeding (due to stress)

  • secondary to hepatic dysfunction → decreased in coagulation proteins or thrombocytopenia

  • hypersplenism from increased portal and splenic vein pressure (will also have splenomegaly due to pooling of cells)

  • altered RBC membranes caused by abnormal blood lipid content in liver disease → spleen will cull or pit these abnormal cells

• associated liver disease

• alcohol intoxication

  • direct toxic effect of ethanol on the developing erythroblasts

how is stimulated erythropoiesis/reticulocytosis associated with nonmegaloblastic anemia?

increased EPO in the presence of an adequate iron supply can result in the release of shift reticulocytes → cells are larger than normal, increase in polychromasia, and oval macrocytes are not present

what is the pathogenesis of hereditary spherocytosis (hemolytic anemia)?

patients will have defects in the membrane cytoskeleton (spectrin, ankryin, band 3, or band 4.2) → since red cell membranes are fragile, the RBCs cannot squeeze through the spleen properly which causes the formation of spherocytosis (eaten by macrophages)

patients who have it mild do not need treatment but it if it severe, a splenectomy can be useful

what would the RBC morphology look like in those with hereditary spherocytosis?

red cells are normochromic and normocytic… depending on patient’s particular genetic defect, there could be a ton of spherocytes (smaller than RBCs and lack central pallor) or just a few

what is the pathogenesis of G6PD deficiency (hemolytic anemia)? (learning objective)

G6PD helps reduce nasty free radicals made during cell metabolism… without enough G6PD around, the free radicals attack the molecular bonds between heme and globin becomes denatured and forms heinz bodies → spleen will pit the heinz bodies, creating a bite cell

• is an intrinsic defect in which the RBC enzymes for maintaining Hb and membrane sulfhydryl groups are deficient in the reduced state for maintaining adequate levels of ATP for cation exchange causing hemolytic anemia

• those who have a deficiency of G6PD are normally ok until they encounter some sort of oxidizing substance like a drug or fava beans

patient must avoid exposure to known oxidants but the hemolysis is self-limiting so it will spontaneously resolve in a week or so

what would the RBC morphology look like in those with G6PD deficiency?

patients going through an acute hemolytic episode will have fragmented cells, microspherocytes, and bite cells → supravital staining will reveal the Heinz bodies

• patients who have not been exposed to offending agents will have no anemia

• heinz bodies will decrease in number as Hb bottoms out because younger cell have greater G6PD activity

what are hemoglobinopathies? (learning objective)

involves abnormal hemoglobin (particularly the beta-chain) and could occur in homozygous or heterozygous forms

what is sickle cell anemia? (learning objective)

an SNP in the beta chain where glutamic acid is replaced by valine at the 6th position → effects of this SNP is a chain in the net charge and electrophoretic mobility which helps ID on Hb electrophoresis

• serious chronic hemolytic anemia due to extravascular hemolysis (increased removal of abnormal cells by the RE system)

• is the most symptomatic hemoglobinopathy and occurs in 1 of every 365 African American births

what are the screening tests to see if a patient has HbS?

• metabisulfite reduction → reducing agent and enhances deoxygenation and sickle cell formation but does not differentiate between heterozygous or homozygous

• the sickle dex test → HbS is less soluble than HbA under decreased oxygen tension which in turn causes the sample to turn opaque but CANNOT tell if a patient has the disease or just the trait — just if the patient makes HbS

  • HbS is released from lysed RBCs and reduced by sodium dithionite

  • false positives can occur from protein disorders

  • false negatives come from only low amounts of HbS being present

what would sickle cell trait and disease look like when using electrophoresis (confirmatory test)? (learning objective)

normal

• will have A2 (<3.7%), HbF (<2%), and HbA

sickle cell trait

• will have A2, HbS (35-45%), HbF, and HbA (50-65%)

sickle cell disease

• will have A2, HbS, HbF, no HbA

remember, a control must be used in electrophoresis too

what are the various treatments in sickle cell anemia? (learning objective)

• avoid dehydration and infection which both cause vaso-occlusion resulting in sickling (preventative)

• blood transfusion (in aplastic crisis or splenic sequestration)

  • could be helpful in preventing complications of SS anemia by suppressing the formation of new HbS by the BM

• hydroxyurea → drug that reduces intracellular sickling

• BM transplant → potential cure

what is the clinical manifestation of sickle cell anemia? (learning objective)

hemolysis and severe pain in the abdomen, bone and joints due to the occlusion of small blood vessels by sickle cell infarcts, otherwise known as a sickle cell crisis

even at physiologic oxygen tension, sickle cell may form

what is the pathogenesis of sickle-cell anemia (hemoglobinopathies)? (learning objective)

abnormal hemoglobin (HbS) in sickle cell anemia will change shape when it releases oxygen, causing it to polymerize and in turn distorting it into a sickle shape

• sickle cells are fragile and will stick together in small vessels (capillaries), leading to ischemia & tissue hypoxia because of a blockage → cells are phagocytized by macrophages (causes the anemia) and the tiny, repeated infarcts in the spleen leads to fibrosis and eventual autosplenectomy

prevent triggers like things that will make RBCs want to give up O2 and vaccination in those who have undergone autosplenectomy

what would the RBC morphology look like in those with sickle-cell anemia? (learning objective)

will often show normocytic, normochromic cells

• during times of crisis/decreased oxygenation, there will be sickled cells in the blood

• when autosplenectomy occurs, there will be a post-splenectomy blood picture which includes NRBCs, polychromasia, Howell-Jolly bodies (due to removal of or a nonfunctioning spleen), sickled cells, and Pappenheimer bodies

what is sickle cell trait? (learning objective)

heterozygous meaning they are a carrier → 8-10% of american blacks are affected (most common hemoglobinopathy in the US) and patient is usually asymptomatic

• clinical symptoms → could appear under conditions of hypoxia: respiratory infections, CHF, anesthesia

what is hemoglobin C? (learning objective)

substitution of lysine for glutamic acid in number 6 position of beta chain and could also be heterozygous or homozygous → mild hemolytic anemia and is mostly asymptomatic with occasional jaundice

what would the RBC morphology look like in those with HbC? (learning objective)

normocytic, normochromic anemia with a high number of target cells (40-90%) and is the most striking feature of HbC… will also have the presence of intracellular rod-shaped crystals (HbC crystals)

what would the electrophoretic profile be in HbC disease and trait?

HbC disease

• HbA → 0%, HbC → almost 100%, HbF → <7%

HbC trait

• HbA → 60-70%, HbC → 30-40%

what is hemoglobin C trait? (learning objective)

heterozygous state (many times they aren’t anemia) → asymptomatic with target cells up to 40% but no HbC crystals

what are heterozygous hemoglobinopathies? (learning objective)

inheritance of different abnormal hemoglobins from each parent results in interactions producing hemolytic anemia of varying disease → HB SC disease which is sickle cell - thalassemia disease (Hb S/beta-thalassemia)

• frequency is similar to sickle cell disease and the severity of the clinical manifestations is intermediate between sickle cell disease and trait

• sickle cell prep is positive

what would the RBC morphology look like in those with Hb SC disease? (learning objective)

anemia will vary from mild to moderate with normocytic, normochromic RBCs, numerous target cells (<85%) and odd shaped cells… will look like there may be sickle cells (rare) and HbC crystals

what is the electrophoretic profile in HB SC disease? (learning objective)

HbA → 0%, HbC and HbS → equivalent, HbF → up to 7%

what is the situation with sickle cell - thalassemia disease (HbS/beta-thalassemia)? (learning objective)

situations of complete absence of beta-chain production (B⁰) are more severe than marked decrease (B⁺)… will have positive sickle cell prep and solubility tests

what is the electrophoretic profile in those with S/B⁰ thalassemia? (learning objective)

HbA → 0%, HbS → 75-90%, HbF → 5-20%, HbA2 → >4.5%

what is the electrophoretic profile in those with S/B⁺ thalassemia? (learning objective)

HbA → 15-30%, HbS → >50%, HbF → 1-20%, HbA2 → >4.5%

what is the pathogenesis of thalassemia? (learning objective)

quantitative disease of Hb (hereditary usually occurring in Mediterranean ancestry like Greece) → impaired production of one or both of a pair of polypeptide chains found in Hb molecules

• structure is normal but there is a decreased rate of synthesis which results in less than normal number of chains and fewer complete Hb molecules

• in thalassemia, patient ends up with a two-fold problem

  • decreased hemoglobin production (due to decrease in globin chains)

  • excess unpaired alpha chains (in beta) or beta, gamma, and delta chains (in alpha) which form tetramers and lead to premature RBC destruction

mild thalassemia doesn’t require treatment but those with severe anemia, patients may need repeated RBC transfusions or even BM transplantation

what is the pathophysiology of beta thalassemia? (learning objective)

beta-chain synthesis is impaired causing an excess of alpha chains which precipitate to damage the RBC membrane → spleen will cull them

• precipitate filled RBCs could be destroyed in the BM by macrophages which results in a large degree of ineffective erythropoiesis

• circulating RBCs with precipitates are removed by the spleen → causes chronic hemolysis

what would the RBC morphology look like in those with thalassemia? (learning objective)

microcytic, hypochromic anemia with a decrease in MCV, MCH, and usually MCHC and an increase in RDW (>14.5%) → will have target cells and microcytosis, basophilic stippling and NRBC (meaning there is aniso and poik)

• reticulocytes (could be stressed retics due to the anemia) and bilirubin usually increased (higher destruction of RBCs)

RBC count is normal or increased for the degree of anemia but will have a decrease in hemoglobin

what is alpha-thalassemia major (also called hemoglobin Barts or hydrops fetalis)? (learning objective)

complete absence of alpha chains which is incompatible with life and is homozygous, meaning both parents must at least carry alpha-globin gene deletions

• no hemoglobin is produced due to alpha chains being required for the formation of hemoglobin

• infants are still born/die in utero due to the child being unable to make normal hemoglobin to carry oxygen throughout the body

  • all four genes for alpha are missing

what counts as hemoglobin Bart’s?

Hb that lacks alpha chains → at least one gene missing

what is alpha-thalassemia-hemoglobin H disease and how would it be treated? (learning objective)

symptomatic (similar to anemia and chronic hemolysis) but nonfatal (normal life expectancy) and occurs when 3 of 4 alpha-genes are deleted → splenomegaly will be present

• treatment would be long-term transfusion therapy and splenectomy (alleviates the anemia when it is removed)

what would the RBC morphology look like in those with alpha-thalassemia-hemoglobin H disease? (learning objective)

microcytic, hypochromic anemia with Hb 8-10 g/dL and will have increased reticulocytes and NRBCs will be present (5-10%)

what is alpha-thalassemia-minor (trait) and what is the treatment? (learning objective)

occurs when 2 of 4 alpha-genes are missing and is found in all geographic locations… patients are asymptomatic with mild anemia

• there is a measurable decrease in the production of alpha-containing hemoglobin BUT unaffected globin genes are able to direct synthesis of globin chains faster than normal and compensate for the affected genes

patients do not require medical intervention and has a normal life span

what is the genetics of thalassemia? (learning objective)

mom is a silent carrier and dad has thalassemia trait

• a silent carrier → only one gene is missing

• thalassemia trait → two genes are missing

• HbH disease → three genes missing

• no anemia → no genes missing

  • child wins the genetic lottery

being a silent carrier or having trait or disease = Hb Barts

what would the what would the RBC morphology look like in those with alpha-thalassemia-minor? (learning objective)

microcytic, hypochromic anemia with a few target cells but could be masked by iron deficiency anemia… to tell the difference, the persistence of microcytes following treatment of iron deficiency anemia is suggestive of thalassemia

what is beta-thalassemia major (homozygous) or Cooley’s anemia? (learning objective)

extreme form of thalassemia where beta-chains cannot be made and is associated with physical abnormalities… onset is generally in infancy with symptoms of irritability, pallor (blue characteristics), and failure to thrive

• anemia will place a tremendous burden on the cardiovascular system due to the increased pumping of blood to compensate for tissue hypoxia… if undetected, cardiac failure can occur

• physical abnormalities → growth is slowed, brown pigmentation of skin, chronic hemolysis which often produces gallstones, gout, and icterus (due to bilirubin build up)

  • will have facial/skull deformities as well due to the marrow cavities enlarging in every bone to accompany the hyperplastic marrow

• will have extramedullary hematopoiesis (spleen, liver) to make more RBCs to compensate… spleen may become enlarged and congested with abnormal RBC

what are the other symptoms of homozygous beta-thalassemia?

• increased metabolic rate

• fever

• lethargy

• weakened musculature

• decreased body fat

• decreased appetite

• infections (common cause of death)

what would the what would the RBC morphology look like in those with homozygous beta-thalassemia? (learning objective)

HB LEVEL IS LOW WITH 2-3 g/dL → anemia is markedly microcytic and hypochromic (MCV <67 with markedly reduced MCH and MCHC and RDW may be increased)… marked aniso and poik and retics are not as increased as they should be because of ineffective erythropoiesis and NRBCs will be present

• secondary leukopenia (decreased leukocytes) and thrombocytopenia (decreased thrombocytes) → will become trapped in the enlarged spleen and is a secondary effect of the spleen

• increased unconjugated bilirubin (will not show up in urine)

body is adapted to the low amounts of Hb and Hb electrophoresis is helpful in diagnosis

what is the treatment for homozygous beta-thalassemia? (learning objective)

regular transfusion program

• prolongs in life in the second or third decade but reduces developmental and growth delays

• iron chelating agents are given to decrease deposition of iron in the tissues

splenectomy

• for patients over 5 → makes them susceptible to infections

prognosis

• untreated patients will die in the first or second decade of life

• patients in hypertransfusion therapy can help extend their life by at least a decade

• second decade patients will develop endocrine disorders (diabetes), and hepatic and cardiac disturbances from excessive iron deposits

what is heterozygous beta-thalassemia minor and the treatment? (learning objective)

heterozygous inheritance meaning they can still produce beta-chains → normal beta-gene directs synthesis of sufficient amounts of beta-chains to make enough HbA for near normal oxygen delivery and RBC survival

• patients appear to be asymptomatic except during periods of stress like pregnancy, infection, and folic acid deficiency

  • can develop a moderate microcytic anemia under these conditions

• patients generally do not require treatment due to being asymptomatic (mostly) and will have a normal life expectancy

what would the what would the RBC morphology look like in those with heterozygous beta-thalassemia? (learning objective)

Hb is 9-14 g/dL which is reduced but not as significant → microcytic, hypochromic RBCs as in IDA with low MCV and MCH… MCHC may be low and RDW is normal, RBC count is elevated but values for Hb and HCT are reduced

• mild to moderate degree of poik, target cells, and basophilic stippling are often found

what are hemolytic anemias? (learning objective)

a group of normocytic, normochromic anemias in which RBC is prematurely destroyed and can be classified according to various things:

• source of the defect

  • intrinsic (immune complex) or extrinsic

• mode of onset

  • inherited or acquired

• location of hemolysis

  • intra- (occurring in the vessels and would appear in the urine) or extra- (spleen, liver won’t see in urine)

• type of poikilocyte

  • schistocytes or spherocytes

what is a constant feature of hemolytic anemia?

reticulocytosis → compensated hemolytic disease in which the BM is able to increase erythropoiesis to compensate for the decreased RBC life span (RBC does not develop)

• will develop into anemia when → RBC destruction accelerates beyond the compensatory capacity of the marrow (hemolytic crisis) and when the marrow suddenly stops producing RBCs (aplastic anemia)

what is the clinical findings in hemolytic anemias? (learning objective)

• pallor, fatigue, and cardiac symptoms

• jaundice due to increase in bilirubin production

• gallstones due to bilirubin

• dark or red urine due to the excretion of plasma hemoglobin (intravascular hemolysis)

• splenic hypertrophy → extravascular hemolysis

what is intravascular hemolysis? (learning objective)

RBC is destroyed within the blood vessels

• Hb is bound to the transport protein → haptoglobin

  • too big to pass through the glomerulus

• when haptoglobin is depleted, hemopexin complexes with Hb

  • too big to pass through the glomerulus

• when haptoglobin and hemopexin are depleted, free Hb appears in the urine (pink, red or brownish black) due to exceeding the renal threshold

  • filtered Hb may be reabsorbed in the PCT

what must happen in order for an RBC to go through intravascular hemolysis and what may it be caused by? (learning objective)

to undergo intravascular hemolysis (happens in the vasculature), RBCs must be severely damaged and may be caused by:

• activation of complement on the RBC membrane (pierces the membrane)

• physical or mechanical trauma to the RBC

• presence of soluble toxic substances in the RBCs environment

what is the lab findings in intravascular hemolysis? (learning objective)

• hemoglobinuria

• hemoglobinemia

• decreased haptoglobin

• decreased hemopexin

• increased LDH-enzyme → present in high concentration in RBCs

what is extravascular hemolysis? (learning objective)

RBCs are removed from the circulation by phagocytes in the tissue and more common than intravascular hemolysis (main mode of hemolysis and Hb will be in macrophages) → may occur in the phagocytes of the spleen, liver, or bone marrow

• no hemoglobinemia and hemoglobinuria

• Hb is degraded with the phagocyte to heme and globin

  • heme is catabolized to iron, biliverdin and CO2 → biliverdin to bilirubin (plasma), binds to albumin, and is excreted by the liver (ex. kernicterus)

• BM macrophages are responsible for the removal of maturing precursor cells that are intrinsically abnormal → cytoplasmic or nuclear maturation abnormalities due to the high degree of ineffective erythropoiesis (iron deficiency and megaloblastic anemia)

what does the type and degree of RBC damage determine in extravascular hemolysis?

determines the primary site of erythrocyte destruction

• spleen is more efficient at removing slightly damaged RBCs

• liver is an important site for the removal and phagocytosis of extensively damaged RBCs

whats a common cause of hemolytic anemia associated with extravascular hemolysis? (learning objective)

antibodies directed against the RBC → antibody and complement attached to the cell membrane making it a target for removal from the circulation by phagocytes

what does the site and extend of extravascular hemolysis dependent on?

class of antibody and the presence of absence of complement

• complement and IgM → removed by the liver due to C3b receptor

  • driver for transfusion reactions

• IgG → removed by macrophages of the spleen

what are the lab findings in hemolytic anemias? (learning objective)

• increase in expired CO

  • increased RBC destruction results in increase heme catabolism and increased production of CO

• increase in carboxyhemoglobin (COHb)

  • COHb is a stable complex of CO that forms in RBCs when CO is inhaled

• increase in bilirubin and urobilinogen

• haptoglobin and hemopexin levels may also be decreased → in severe or chronic conditons

what are intrinsic defects in hemolytic anemias? (learning objective)

abnormality of the RBC itself → most are hereditary and is in extravascular hemolysis… cells are more susceptible to damage by environmental factors

• structural defects may cause the membrane to become abnormally permeable, rigid, or unstable and easily fragmented and ultimately hemolysis

what is paroxysmal nocturnal hemoglobinuria? (learning objective)

an intrinsic defect in which the RBC lacks a protein that controls complement attachment and activation (acquired abnormality)

will have normocytic or macrocytic: microcytic, hypochromic if Fe deficient

what are extrinsic defects in hemolytic anemias? (learning objective)

usually acquired → RBCs are damaged by chemical, mechanical, or physical agents and hemolysis could be intravascular or extravascular

what are chemical extrinsic effects in hemolytic anemias? (learning objective)

substances in the circulation that are toxic to the cell and causes direct cell hemolysis or alter cell membranes and lead to removal of the cell in the spleen

what are mechanical trauma extrinsic effects in hemolytic anemias? (learning objective)

trauma to the RBC may cause the RBC to fragment which produces striking abnormalities on the blood smear… splenomegaly may cause anemia to hyper-sequestration of RBC

what are physical agent extrinsic effects in hemolytic anemias? (learning objective)

antibodies or complement attached to the RBC membrane sensitized the cell which caused premature removal by macrophages in the spleen or liver… can be autoimmune, alloimmune, or drug induced

what do all immune anemias have? (learning objective)

all have a positive DAT due to immunoglobulin or complement on the cell

what is the pathogenesis of autoimmune hemolytic anemia? (learning objective)

warm

• patient makes IgG anti-RBC antibodies which binds at 37C best which is warm

• splenic macrophages will think that the antibody-coated RBCs are appetizing and will either cull or pit them

cold

• patient makes IgM anti-RBC antibodies that bind at <37C which means they will bind in distal body parts but fall off in warm body parts

• IgM will bind a bunch of RBCs together which forms clumps and complement will bind to the RBCs too → causes intravascular hemolysis