CMPP: Hemolytic Anemias Part 2

porphyrin ring

Fe2+

what is included in the heme portion of hemoglobin?

2 alpha chains

2 beta chains

--> 4 globin polypeptide chains

what is included in the globin portion of hemoglobin?

4

one hemoglobin molecule can carry how many oxygen molecules?

alpha, beta, gamma, delta

types of globin subunits

Methemoglobin

Fe3+ containing hemoglobin that cannot combine oxygen.

alpha2/gamma2

--> majority of Hgb after 14 wks gestation

fetal hemoglobin is made of what globin subunits?

after 6 mo old

when does fetal hemoglobin transition into adult Hgb

2 alpha globin genes (4 alleles) -- chromosome 16

single beta globin gene (2 alleles) -- chromosome 11

what is the "genetic makeup" of hemoglobin?

Oxygen dissociation curve

represents how easily hemoglobin gives up its O2

loading, higher, discourages

--> this occurs during processes in which the cells are good on oxygen

a left shift in the oxygen dissociation curve favors oxygen ________, has a _______ O2 affinity, and _________ O2 release

unloading, lower, encourages

--> this occurs in states in which there is a high metabolic demand (illness, acidotic), so more oxygen is needed to be given up, and CO2 must be collected due to a high pCO2

a right shift in the oxygen dissociation curve favors oxygen ________, has a _______ O2 affinity, and _________ O2 release

Bohr effect

states that the affinity fo normal hemoglobin for oxygen is inversely related to acidity and carbon dioxide concentration

THEREFORE:

> affinity for oxygen, decreased acid/CO2

< affinity for oxygen, increased acid/CO2

in utero -- fetal hemoglobin is better at holding onto O2, so, babies leech off of mom's lower affinity HgA1, so they can get oxygen

-->fetal Hb oxygen affinity allows for transfer of oxygen between mother's blood and developing fetus

what is the clinical significance of fetal vs adult hemoglobin?

Hemoglobin electrophoresis

blood test used to identify types of hemoglobin present in sample; quantifies how much of each hemoglobin type is present

hemoglobin is negatively charged -- electrical current allows them to sort themselves by different charges

band pattern reviewed to determine type and quantity of hemoglobin present

how does hemoglobin electrophoresis work/separate Hgb?

Thalassemia

collection of disorders with a disrupted ratio between alpha ad beta chain production (reduced or absent production of one of the globin chains) that is autosomal recessive; has a high prevalence in Greek, Italian, Middle Eastern, Asian, African (Mediterranean sea)

excess unpaired globin chains precipitate inside RBC precursors --> premature hemolysis occurs

how does the absent/reduced production of one of the globin chains affect the RBC?

2, 16, insoluble, beta

alpha globin comes from ___ genes on chromosome __. free alpha chains are ______, and they occur in ______ thalassemia

single, 11, soluble, alpha

beta globin comes from a _____ gene on chromosome __. free beta chains are _____, and they occur in _____ thalassemia.

microcytic

what is the expected MCV range for thalassemia?

iron deficiency anemia

what is the #1 cause of microcytic anemia?

if the microcytic anemia was caused by an iron deficiency, RDW would be high, if it was caused by something genetic (thalassemia), it would be low

why does RDW help to narrow the diagnosis of a microcytic anemia?

Target cells

cells with a dark center with a clear ring between the dark center and the periphery of the cell; characteristic of thalassemia

Alpha thalassemia

Diseases in which there are insuffiecient alpha-globin chains due to gene deletions, which leads to an excess of beta chains in adults and an excess of gamma chains in infants

tetramers, unstable, precipitate

in alpha thalassemia, excess beta chains can form _____, while they are soluble, they are ______ and can ________ within the cell

alpha chains

are alpha or beta chains more toxic?

microcytic -- low volume due to chronic destruction of RBCs

hypo chromic -- less amount of Hb per cell so less color

what are some characteristics of the RBCs in alpha thalassemia?

Basophillic stippling

basophilic granules dispersed in RBCs; indicates disrupted erythropoiesis; dots are an accumulation of RNA fragments

hemolytic anemias

alpha or beta thalassemia

lead poisoning

in what conditions does basophilic stippling occur?

Wright stain

what stain is used to identify basophilic stippling?

Alpha thalassemia trait

also known as silent carrier (aa/a-); have an asymptomatic presentation and normal hematologic findings

DNA analysis (can be found incidentally if another family member has a more serious case of thalassemia)

how is alpha thalassemia trait diagnosed

prophylactic folic acid supplement

how is alpha thalassemia trait treated

Alpha thalassemia minor

aa/-- OR a-/a-; asymptomatic; can see target cells on peripheral smear; can have mild Anemia

prophylactic folic acid supplement

treatment for alpha thalassemia minor

Hemoglobin H disease

a-/--; HbH tetramers result from excess beta chains

high, left reduced

HbH tetramers have a _____ affinity for oxygen (____ shift), which results in a ________ability to supply O2 to tissues

readily oxidized -- hemolyze in times of oxidative stress

how is HbH more unstable than HbAI

at birth neonatal jaundice and anemia

Hemoglobin H disease presents when with what symptoms?

hemolytic anemia, iron overload, hepatosplenomegaly

--> due to unstable nature, disruption to iron absorption, and risk for sequestration of blood cells

patients with Hemoglobin H disease are susceptible to what symptoms and why?

HbF

Alpha2 Gamma2

ineffective erythropoiesis and blood transfusions for tx

why is there a risk for iron overload with alpha thalassemia intermedia

avoid oxidative stress

minimize infixes (vaccinate)

prophylactic folic acid supplementation

follow labs

blood transfusions for severe cases (but be careful, as these patients can become transfusion dependent and will need iron chelation)

splenectomy -- SEVERE cases

treatment for Hemoglobin H disease

alpha thalassemia major

condition in which the patient is unable to make ANY alpha chains; cannot synthesize HbA, HbF, HbA2

Hb Barts

tetramer consisting of 4 gamma globulins in which the O2 affinity is 10x greater than HbA; therefore binding O2 but cannot transport it to tissue; NOT COMPATIBLE WITH LIFE, as fetal demise occurs typically in late second/early third trimester

survival possible with intrauterine transfusions, chronic transfusions and stem cell transplant

treatment for Hb barts

Beta thalassemia

impaired production of beta chains; defect in beta globin gene on chromosome 11; this leads to an excess of insoluble alpha chains.

unstable, precipitate immediately, within the bone marrow

alpha chains are _____ and __________ within the RBC, which destroys RBC precursors ________________.

6 months

symptoms of beta thalassemia begin around...

fetal hemoglobin is gamma/alpha -- don't start producing beta until this age

why does beta thalassemia begin showing symptoms at 6 months?

Beta thalassemia minor

defect in one beta allele that causes one to be an asymptomatic carrier; heterozygous

ranges from asymptomatic, marked microcytosis with a disproportionately mild anemia, and target cells

clinical presentation of beta thalassemia minor

RBC count is HIGH in beta thalassemia minor

Retic count is normal to slightly increased in beta thalassemia minor

how to differentiate beta thalassemia minor from iron deficiency anemia

because the cells are so microcytic they need more oxygen, so, more RBCs are produced to compensate for the lack of oxygen being carried/transported by the defective cells

why is RBC count elevated in beta thalassemia minor?

no specific tx -- may occasionally need transfusion if pregnant

watch for iron tx -- only if they have a true iron deficiency!

treatment for beta thalassemia minor

Beta thalassemia intermedia

thalassemia in which symptoms are present but mild; anemia is present but not initially transfusion dependent

iron overload (releasing more iron to make more blood cells)

extra medullary hematopoiesis and therefore hepatosplenomegaly

hemolysis

in Beta thalassemia intermedia, ineffective erythropoiesis can result in...

Folic acid supplementation

monitor and support any progression of anemia -- may need transfusion during growth spurts, pregnancy, and oxidative stress

NOT transfusion dependent, but can become

monitor for iron overload due to repeated transfusions/abnormal iron absorption -- iron chelation

splenectomy reserved for SEVERE cases

Beta thalassemia intermedia tx

Cooley's Anemia (Beta Thalassemia Major)

thalassemia that results from 2 defective beta alleles, and absent beta globin production leads to excess unpaired alpha chains that are unstable and precipitate immediately within the RBC

intramedullary hemolysis (destruction of RBC precursors)

intravascular hemolysis

what causes the profound anemia associated with beta thalassemia major?

erythroid hyperplasia (cells made much more rapidly)

extra medullary hematopoiesis (cells are made elsewhere)

how does the body attempt to compensate for the profound anemia associated with beta thalassemia major?

EPO, beta chain, expanding sites of hematopoiesis (extra medullary hematopoiesis)

Excess demand associated with Cooley's anemia results in excess ____ production. Hematopoietic cells in the bone marrow try to respond but cannot without ________ production. So, the body responds by....

Extramedullary hematopoiesis

expansion of hematopoiesis outside the medulla of the bone marrow

liver lymph nodes, spleen, diaphysis, shaft, and periosteum of long bones

common sites for extramedullary hematopoiesis

bony masses, pathologic fractures, or bone pain

Extramedullary hematopoiesis in the diaphysis, shaft, and periosteum of long bones can manifest as what symptoms?

6 months of age, since beta chains aren't being made until then

beta thalassemia major presents at...

pallor, jaundice, growth retardation, abdominal swelling

presentation of Cooley's anemia in those < 2y/o

delayed skeletal maturation due to extramedullary hematopoiesis

--> marrow space widens and osteoporosis occurs

why is there growth retardation associated with Cooley's anemia?

Chipmunk face

characteristic of beta thalassemia characterized by wide spaced eyes, prominent forehead, overgrowth of maxillae

hair on end appearance skull

what are the radiologic findings associated with beta thalassemia major?

accentuated trabeculae due to bone marrow hyperplasia

why does hair on end appearance skull happen in beta thalassemia?

low - bone marrow is failing :(

elevated -- bone marrow is trying to make more and more blood, so it brings out more and more iron

Beta thalassemia major is a profound hypochromic microcytic anemia. Lab findings include a ___ reticulocyte count, and an ______ serum iron and ferritin

only HbF/HbA2 present since beta is not being made

--> would show donor blood if patient was getting transfusions

what are the Hb electrophoresis results associated with beta thalassemia major?

folic acid supplementation

chronic blood transfusions (transfusion dependent)

monitor complications -- iron overload (chelation), osteoporosis

splenectomy for SEVERE cases

bone marrow transplant

beta thalassemia major treatment

bone marrow transplant - reserved for severe cases

what is the ONLY CURE FOR BETA THALASSEMIA MAJOR

Iuspatercept (Reblozyl)

newly approved for transfusion-dependent beta-thalassemia

promotes RBC maturation and makes RBCs more efficient

reduces transfusion requirements

Iuspatercept (Reblozyl) MOA

thromboembolism (DVT/CVA)

bone pain/arthralgias

adverse effects of Iuspatercept (Reblozyl)