ferritin, transferrin, Fe3+ - Absorbed iron is converted to _______ for storage or transported a ___________. In both cases, iron exists in the ____ form.

heme, Fe2+, globin, hemoglobin - Ferritin can be transferred to be transported by transferrin to the bone marrow, where iron is incorporated into __x__ synthesis. Fully formed __x__ molecules contain iron in the ____ state and is bound to ______ to create __________, which is then incorporated into mature RBCs and transported as plasma transferrin.

iron - Erythropoiesis is dependent on

ferritin, hemosiderin - ____x____ is a protein with a capacity of about 4500 Fe3+ ions per protein molecule. This is the major form of iron storage. If the capacity for storage of iron in ____x____ is exceeded, a complex of iron forms. This is called ___________; a lipophilic protein that releases Fe3+ slowly and is observed in tissue stained with Prussian blue

hemosiderin - a lipophilic, insoluble iron aggregate derived from ferritin

labile iron, apoferritin, ferritin, hemosiderin, - Iron (deposition) is transported across the cell membrane and forms __x__ __y__, which is bound to ___________ to form ____z____. Some iron is converted to ___________ and stored into cells, some iron is released back to ____z____, back to __x__ __y__ state, and is released across the membrane so iron is mobilized and circulating in the blood.

serum [Fe] - measure of transferrin-bound Fe

TIBC - total amount of Fe that can be bound by transferrin in plasma/serum

UIBC (Unsaturated Iron Binding Capacity)+ SI (Serum Iron;measured) - TIBC =

%saturation - %transferrin saturation with Fe

(serum iron/TIBC)*100 - %saturation =

Serum [Fe], TIBC, %saturation - Routine Iron Panel

serum ferritin - directly proportional to the amount of Fe stored

Transferrin receptor - inversely proportional to total Fe

FEP (free erythrocyte protoporphyrin) - a heme precursor that conjugates iron into hemoglobin

(pre-latent) stage I (iron depletion) - Stage of IDA:

-Reduction in iron stores without reduced serum levels

-Hb, MCV, transferrin saturation: Normal

-Iron absorption: Increased

-Serum ferritin and marrow iron: Decreased

-No clinical manifestations: normocytes, normochromia, RDW normal

(latent) stage II (iron deficiency erythropoiesis) - Stage of IDA:

-Iron stores are exhausted; the blood hemoglobin level remains normal but serum Fe is decreased

-Normocytes, normochromia, RDW normal

(iron deficiency anemia) stage III - Stage of IDA:

-Blood hemoglobin concentration falls below lower limit: Decreased MCV, MCH, MCHC

-Clinical manifestations in the form of sideropenic syndrome

-Microcytes, hypochromasia, increased RDW

sideropenic syndrome - Clinical manifestations of iron deficiency anemia are in the form of

increases - As iron deficiency progresses, TIBC [increases/decreases]

decrease - As iron deficiency progresses, marrow iron stores, ferritin, and serum iron [increase/decrease]

microcytic, hypochrmic - By stage III of iron deficiency anemia, RBC are ___________ and ____________

decreased - By stage III of iron deficiency anemia, %saturation, reticulocyte count, and RBC indices are [increased/decreased]

increased - By stage III of iron deficiency anemia, RDW is [increased/decreased]

pre-latent (iron depletion) - Iron deficiency anemia patients can test positive for stool-occult blood by the ________ stage

45% - Normal Hematocrit

(Patient Hct%*Reticulocyte%)/45% - Corrected Reticulocyte Count =

Pt Hb*(Pt Hct/Standard Hct))/Maturation Correction - RPI =

underproduction, MCV - If RPI is <2%, there is a(n) ______________ of RBCs and the ___ must be measured.

increased destruction/loss - If RPI is >2%, there is a(n) ______________ of RBCs and further workup must be down based on history, physical, etc.

hemosiderosis - an abnormal increase of iron in the blood caused by the large breakdown of red blood cells resulting in an accumulation of hemosiderin

hemochromatosis - disorder characterized by iron accumulation in reticuloendothelial cells in tissues, resulting in organ damage (heart, liver, pancreas, pituitary, joints...)

transfusion hemosiderosis, idiopathic pulmonary hemosiderosis (Good pasture's syndrome, Wegener's granulomatosis) - Hemosiderosis can be caused by:

hereditary, secondary - Hemochromatosis can be classed as __________, most likely due to a defect in the hepcidin gene, or _________, (example:) as a result from frequent blood transfusions

anemia of chronic disease - caused by chronic inflammation due to chronic infections or autoimmune diseases; associated with decreased erythropoitein and malignant neoplasms.

iron, ferritin, erythroid precursors - In anemia of chronic disease, inflammatory cytokines block ____ transfer from ________ to _________ __________

anemia of chronic disease - Serum Fe: decreased

TIBC: decreased

%Saturation: decreased

Serum ferritin: increased

RBCs: variable (normo, micro...)

Increased BM Fe stores with decreased sideroblasts

sideroblastic anemia - group of blood disorders characterized by deficient enzymes involved with porphyrin synthesis, causing iron to accumulate in mitochondria; can be acquired or inherited as sex-linked or autosomal recessive

acquired primary - Sideroblastic anemia that is idiopathic; e.g., myelodysplasia (RARS)

acquired seconary - Sideroblastic anemia that can be caused by chronic alcoholism, lead toxicity, certain medications; e.g., chloramphenicl

sideroblastic anemia - Serum Fe: increased

TIBC: decreased

%Saturation: decreased

Serum ferritin: increased

RBCs: dimorphic with marked hypochromasia

Anisocytosis, basophilic stippling; normal RBC indices with increased RDW

Hypercellular BM due to erythroid hyperplasia

hereditary, acquired, secondary - Hemochromatosis can be _________, ________ though repeated PRBC transfusions, or ________ to hemolytic anemias (SS, thalassemia, HS, sideroblastic anemia, enzyme deficiency porphyrins)

hereditary hemochromatosis - autosomal recessive blood disorder; one of the most common inherited diseases

hemochromatosis - Serum Fe: increased

TIBC: normal or increased

%Saturation: increased

Serum ferritin: increased

RBCs: indices, morphology, & H/H normal

Serum enzymes: increasing as disease advances

dUMP, thymidylate synthase, methylene-THF, dTMP - 1. __x__ is the substrate for the enzyme ___________ ________, which takes a methyl group from ____________ and conjugates it to __x__, forming ____.

THF, homocysteine, methionine, 5-methyl-THF, serine hydroxymethyl transferase, methylene-THF - 2. ___ is generated by ____________ converting to __________ and transferring methyl group and sourced form ____________. Another enzyme, ______ ______________ ____________, forms ______________.

methylene-THF, DHF, THF, DHFR, - 3. The demethylation of _____________ results in ___ which is converted back to ___ by the enzyme ____; involves cofactors NADPH releasing proton to form NADP

5-methyl-THF, THF, methyl transferase, cobalamin (B12), methylcobalamin, methionine, homocysteine - 4. The ____________ is converted to ___ by ______ ______________, which methylates _________, forming _______________, continuing to reaction to __________ back to ____________.

defective DNA synthesis (a nuclear maturation defect) - Megaloblastic anemias are associated with _________ ___ _________ and therefore, abnormal RBC maturation in the bone marrow

TTP (thymidine triphosphate) - The primary defect in DNA replication in megaloblastic anemia is usually due to depletion of __ which leads to retarded mitosis, and therefore retarded nuclear maturation

vitamin b12, folate - The depletion of TTP (thymidine triphosphate) is usually due to a deficiency of _______ ___ or ______, allowing the cytoplasm to mature while DNA synthesis is defective (disruption of Chargaff's rules A=T, G=C).

nuclear-cytoplasm asynchrony - A vitamin b12 or folate deficiency allows the cytoplasm to mature while DNA synthesis is defective. This leads to

dUMP - the substrate for the enzyme thymidylate synthase that donates a methyl group to form dTMP

thimidylate synthase - Enzyme that demethylates dUMP to form dTMP

IF (intrinsic factor), GIT, ileum, pinocytosis, liver - Vitamin B12 (Cobalamin) binds to the glycoprotein _x_ in the stomach that is synthesized by parietal cells. B12 combines with _x_, forming a complex that resists digestion by ___ enzyme. Complex is absorbed at terminal _____ by ___________.

B12 is then transported to ____ where it is stored.

megalob(12)lastic, pernicious (p=parietal) - ____________ anemia is a deficiency of B12.

__________ anemia is caused by an inadequate production of IF by parietal cells.

inadequate dietary intake (vegetarians), inadequate production of intrinsic factor (pernicious anemia), malabsorption - Reason for B12 deficiency:

inadequate dietary intake, malabsorption, excess demand (pregnancy, malignant tumors) - Reasons for folate deficiency:

anti-parietal cell, anti-intrinsic factor - Pernicious anemia immune abnormalities: two types of antibodies

blocking antibodies, which block the binding of B12 (cobalamin) to IF, and binding antibodies, which bind to the B12-IF complex and prevent the complex from binding to receptors in the ileum - Anti-intrinsic factor antibodies cause pernicious anemia in two ways:

hypersegmented neutrophils, high MCV, normochromic ovalocytes and macrocytes (not always macro) (also hypercellular BM, low M:E ratio, pancytopenia, HJ bodies, cabot rings)

giant bands and metamyelocytes - Megaloblastic anemia presents with: (4 major+)

Megaloblastic anemia also presents with ______________________________________ because nuclear development is asynchronous

folate deficiency - Certain drugs can result in _____ __________: phenytoin, trimethoprim, methotrexate, oral contraceptives

aplastic anemia - a disease in which the bone marrow, and the blood stem cells that reside there, are damaged, resulting in pancytopenia

acquired idiopathic, acquired secondary, congenital - Classifications of Aplastic Anemia:

PNH (paroxysmal nocturnal hemoglobinuria) - acquired idiopathic aplastic anemia pathology

drugs, radiation, infections - acquired secondary aplastic anemia pathology

Fanconi's anemia - congenital aplastic anemia pathology

low - All values (H&H, absolute retic, corrected retic, wbcs, platelets) are [high/low] in aplastic anemia

hypocellular, stroma, lymphocytes, plasma - In aplastic anemia, the bone marrow is ____________. Marrow is ______ with primarily __________ and ______ cells

PNH (paroxysmal nocturnal hemoglobinuria) - caused by an acquired genetic defect limited to the stem-cell compartment affecting the PIGA gene.

Mutations in the PIGA gene renders cells of hematopoietic origin sensitive to increased complement lysis.

PIGA, GPI anchoring proteins - PNH (paroxysmal nocturnal hemoglobinuria) is caused by a mutation in the ____ gene resulting in a lack of ___ _________ ________.

C3b, complement-mediated hemolysis, complement fixation - Normal RBCs are protected from ___ binding and ___________________ _________ because the PIGA anchored proteins CD59 and CD55 are present and thus __________ ________ cannot occur

CD55, CD59, GPI anchoring, - The PNH cell has decreased ____ and ____ protein on the cell service due to lack of ___ _________ proteins, allowing for C3b binding and complement fixation that leads to red cell lysis.

intravascular hemolysis, hemoglobinuria - PNH is characterized by spontaneous complement activation resulting in MAC-mediated _____________ and _______________

CD55, CD59 - ____ and ____ protects RBCs from intravascular hemolysis

normocytic, normochromic - PNH is [micro/normo/macro]cytic and [micro/normo/macro]chromic

Ham's Test (acidified serum lysis test) - The complement present in serum is responsible for lysis of PNH cells with sensitivity to acidification.

Test for PNH where patient red cell suspension + mixed with fresh complement, acidified at pH 6.5 and body temperature for 1 hour.

positive - Lysis in the Ham's test for PNH is [positive/negative]

negative - No lysis in the Ham's test for PNH is [positive/negative]

Sugar water test - Test for PNH where patient red cell suspension + control serum + sucrose at room temperature for 1 hour.

positive - Hemolysis in the Sugar Water test for PNH is [positive/negative]

negative - No hemolysis in the Sugar Water test for PNH is [positive/negative]

Fanconi's anemia - Aplastic anemia with bone abnormalities (radius, thumbs), short stature, renal malformations, microcephaly, hypogonadism, and brown pigmentation of skin.

Very rare congenital form of a plastic anemia (autosomal recessive). Presentation at age 5 to 6 years. Can transform to acute leukemia.

HS (hereditary spherocytosis), deficiency in G6PD, thalassemias (hemoglobin defect) - Intracorpuscular reasons for intravascular hemolysis

tranfusion reactions, drug-associated reactions - autoimmune extracorpuscular reasons for extravascular hemolysis

Fragmentation Syndromes: TTP(Thrombotic thrombocytopenic purpura)/HUS(hemolytic uremic syndrome), DIC(disseminated intravascular coagulation) - non-autoimmune extracorpuscular reasons for extravascular hemolysis

spleen, RES, senescent - Extravascular red cell destruction occurs in the ______ borne by ___ cells (macrophages) that are destroying _________ RBCs.

hemolysis - As long as haptoglobin is not bound to hemoglobin, that means there is no ________.

glucoronic acid, glucoronyl transferase, bilirubin glucoronide - Unconjugated bilirubin is lipophilic and is conjugated to __________ ____ by __________ ___________, making hydrophilic _________ ____________

increase (>2.0), Coombs' test, autoimmune hemolytic anemia, peripheral blood smear - Hemolysis causes an [increase/decrease] in RPI.

Increased RBC destruction → Increased RBC production.

A _____ ____ must be performed. If positive, __________ _________ ______ is present. If negative, a __________ _____ _____ is needed to assess RBC morphology.

right, left - Osmotic fragility is increased if there is a shift of the curve to the [left/right].

Osmotic fragility is decreased if there is a shift of the curve to the [left/right].

hereditary, ABO incompatibility, autoimmune hemolytic anemia, infections, severe burns, DIC, HUS - Spherocytosis can be __________.

Can also be caused by... (6)

36 - Hereditary spherocytosis MCHC > __

NADPH, hemolysis, ATP - G6PD (glucose-6-phosphate dehydrogenase) deficiency impairs the ability of an erythrocyte to form _____, resulting in _________ and will prevent the cell from generating sufficient ___.

Hemoglobinopathy - blood disorder which involves a single nucleotide point mutation in the genetic code of the globin gene, resulting in structural abnormalities in the globin proteins

Hb A, Hb F - The beta gene of hemoglobin needs to be transcribed to form ___ and the gamma gene needs to be transcribed to form ___ on Chromosome 11

valine, glutamic acid - The single nucleotide polymorphism in Hemoglobin S occurs at the 6th position of the amino acid sequence.

______ substitutes for _______ ____.

sickle cell trait (Hgb AS) - Clinically normal presentation; acute vasoocclusion occurs only under extreme conditions (vigorous exertion at high altitude). Sometimes presents with painless hematuria in adolescent males.

sickle cell trait (Hgb AS) - CBC and PBS normal in diagnostic testing; hemoglobin electrophoresis shows that Hgb S compromises ~40% of hemoglobin and Hgb A 60%. No treatment necessary.

sickle cell anemia (Hgb SS) - elevated serum unconjugated bilirubin and lactase dehydrogenase (LDH); serum haptoglobin low

sickle cell anemia (Hgb SS) - hematocrit usually 15-30%, retic elevated.

PBS: sickled cells, reticulocytosis, nucleated RBCs, howell-jolly bodies, target cells

WBC elevated, thrombocytosis may occur

HB electrophoresis 100% S

vaso-occlusive crisis, hand-foot syndrome, hemolytic anemia, organ ischemia, acute chest syndrome, stroke (+pain) - consequences of sickle cell anemia: (5)

sodium metabisulfite - Mixing blood with the reducing agent ______ _________ induces sickling in susceptible cells in the Sickle Solubility test

Hb S - The Sickle Solubility test only detects...

Hb C Harlem, unstable hemoglobin, low hemoglobin - causes of false positives in the sickle solubility test

children, low HbS <20% - causes of false negatives in the sickle solubility test

sickle solubility, hemoglobin electrophoresis - The _______ __________ test does NOT distinguish between sickle cell disease and sickle cell trait;only __________ _______________ does that

Hb A - Sickle Solubility Test results:

If the individual is ___ there will be no precipitation of the Hb and the solution will appear transparent

Hb S - Sickle Solubility Test results:

If ___ is present, the reagent sodium metabisulfite will cause the sickled cells to precipitate and the solution will become turbid

lysine, glutamic acid - The single nucleotide polymorphism in Hemoglobin C occurs at the 6th position of the amino acid sequence.

_____ substitutes for ______ ____.

Hb C - ___ shows rectangular crystals of RBCs in the PBS due to hemoglobin precipitating to one side of the cell

less, underproduction, <80, microcytic - In Thalassemias, RI is [greater/less] than 2% because there is an ________________ of RBCs and so the MCV is ___, classifying thalassemias as a __________ anemia

hypochromic, microcytic, poikilocytotic, target cells, nucleated RBCs - In a thalassemia peripheral blood smear, RBCs are ___________, ___________, and _______________ because there is too little hemoglobin. ______ _____ and __________ ____ are also observed.

⍺2β2, 97% - Adult hemoglobin Hb-A structural formula and percentage

⍺2δ2, 1.5-3.2% - Adult hemoglobin Hb-A2 structural formula and percentage

⍺2ɣ2, 0.5-1% - Fetal hemoglobin Hb-F structural formula and percentage

beta, alpha deletions, 16 - Alpha thalassemias are caused by excess ____ chains due to _____ _________ on chromosome __

alpha, mutations, 11 - Beta thalassemias are caused by excess _____ chains due to ___________ on chromosome __

beta, β4 (hemoglobin H), alpha - In Hemoglobin H (HbH) (alpha thalassemia) disease, excess ____ chains precipitate as __ inclusion bodies in the cell. In beta thalassemia major, excess _____ chains can also precipitate as inclusion bodies.

Heinz bodies - A type of inclusion body containing denatured hemoglobin. Classically associated with a G6DP deficiency, these can also be found in the thalassemias. When a functional spleen is present, these lead to bite cells.

Howell-jolly body - A type of inclusion body containing DNA. Usually removed by splenic macrophages. Can be seen when red cells fail to fully mature or when a functional spleen is absent.

Normal - Chromsome 16: 4 functional alpha genes

⍺⍺/⍺⍺

silent-alpha-thalassemia (carrier) - Chromosome 16: 3 functional alpha genes

⍺-/⍺⍺

alpha-thalassemia trait (minor) - Chromosome 16: 2 functional alpha genes

Homozygous inheritance of ⍺+: ⍺-⍺-

Heterozygous inheritance of ⍺0: --/⍺⍺

HbH disease (β4) (deletional) - Chromosome 16: 1 functional alpha gene

--/-⍺

Hb Bart's Hydrops Fetalis (fatal) (major) - Chromosome 16: 0 functional alpha genes

--/-- or ɣ4

silent-alpha-thalassemia (carrier) - Alpha thalassemia with a normal MCV, no anemia, and a normal Hb electrophoresis with <3% Hb Barts at birth

alpha-thalassemia trait (minor) - Alpha thalassemia with a low MCV, mild anemia, and a normal Hb electrophoresis with 3-8% Hb Barts at birth

HbH disease (β4) (deletional) - Alpha thalassemia with a low MCV, moderate anemia, and 5-30% HbH present in Hb electrophoresis with 20-40% Hb Barts at birth

Hb Bart's Hydrops Fetalis (fatal) (major) - Alpha thalassemia with a low MCV, fatal anemia, and Hb Barts and HbH present in Hb electrophoresis. HbA, HbF, and HbA2 are absent.

beta thalassemia - The result of deficient or absent synthesis of beta-globin chains, leading to excess alpha chains. Controlled by one gene on each chromosome 11.

beta-gamma switch - The two gamma globin genes are active during fetal growth and produce Hemoglobin F. The "adult" gene, beta, takes over after birth. This is known as the

decreased, increased, increased - In major and minor beta thalassemia, Hgb A is [increased/decreased], Hgb A2 is [increased/decreased], and Hgb F is [increased/decreased]

major is a more DRAMATIC inc/dec

beta, alpha, Hgb F - In severe beta thalassemia, there is decreased [alpha/beta] production. Excess [alpha/beta] damages precursors in marrow, causing ineffective erythropoiesis. Selective survival of cells produces ___ _.

alpha, intravascular hemolysis - In severe alpha thalassemia, or Hemoglobin H disease, there is decreased [alpha/beta] production. Hemoglobin H is detectable in blood; precipitates and damages RBCs, causing _____________ _________

Hemoglobinopathies, Thalassemias - __________________ typically have at least one amino acid substitution leading to synthesis of a variant globin chain. ____________, on the other hand, involve perturbation of the rate of globin chain synthesis

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