Anemias: Quiz yourself all about it
What three serum findings can each independently justify a diagnosis of anemia?
RBC count, hematocrit, or hemoglobin content of RBC's
know anemia from CBC:
RBC male < 4.5 million, female < 4.0
HCT male < 42%, female < 37%
HGB male < 14 g/dL, female < 12 (< 11 in preg female, <13 in male per Wiggin)
If the RBC, HGB or HCT is low, what do you look at next?
MCV and MCHC to see if it's microcytic hypochromic, normocytic normochromic, or macrocytic
If the MCV is low and it's micro-hypo, what do you test next?
serum iron, TIBC, ferritin, BM biopsy, HGBE (electrophoresis of HGB, also indicated by sickle cells, target cells, or nucleated RBC's)
If MCV is in normal range (80-100 fL) then what do you check next?
serum iron, TIBC, then retics, haptoglobin, Coomb's test
If the MCV is over 100 and you have a macrocytic anemia, what do you check next?
retics, serum B12 & folate
What are the three most common causes of anemia?
iron deficiency, thalassemia, and anemia of chronic dz
If there are spherocytes in the CBC differential, what tests do you order?
Coombs test (for immune mediated hemolytic anemia) and Osmotic fragility test (for HS)
If there are nucleated RBC's present, what tests do you order?
HGBE and BM biopsy
What other labs are standard to order for anemia?
(besides the CBC and peripheral blood smear eval: retic count, stool occult blood, and urinalysis (looking for bilirubin/hemolysis or bence-jones proteins/immune issue)
Why might a normal ferritin not exclude a diagnosis of iron deficiency anemia? ???
What bone tissues are responsible for cleaning up old and malfunctioning RBC's?
spleen, liver, and bone marrow phagocytes
How long do RBC's normally live and circulate?
90-120 days
What is heme degraded to when a RBC is recycled?
bilirubin
What are two variables that provoke erythroppoietin (EPO) production from the JGA of the kidneys?
decreased O2 and increased androgens
How much can the bone marrow increase RBC production over baseline?
7-8x
How much of a RBC is hemoglobin?
90%
About what % of peripheral RBC's should be RETICS (immature/just released)?
.5-1.5%
What are the three main mechanisms of anemia?
blood loss (acute or chronic), deficient erythropoiesis, and excessive hemolysis
What part of the hemoglobin complex links temporarily to oxygen molecules?
the iron of the heme group
What are some signs of bleeding?
melena = stools or vomit stained black by blood
hematochezia = bloody feces
epistaxis = nose bleed
hematemesis = vomiting blood
menorrhagia = abnormally heavy or prolonged menstruation
What are some signs of increased hemolysis?
jaundice, dark urine
What are some symptoms of low oxygen transport capacity?
pallor, fast or weak pulse, SOB, palpitations,
dizziness, fatigue, headaches, faintness or syncope
What's the nutritional difference between internal and external blood loss?
With an internal bleed, the heme can be recycled, but with an external bleed the body is reliant on iron stores to supply RBC production
What three body systems are the usual locations for chronic hemorrhage?
--GI (ulcer, colitis, cancer), gyne (excessive menses or cancer), and GU (cancer or stone)
What are some possible causes of microcytic RBCs? (MCV < 80 fL)
--altered heme or globin synthesis (thalassemia, sickle cell, porphyria)
--iron deficiency
--anemia of chronic dz (not always)
What are some causes of macrocytic RBCs? (MCV > 95 fL)
--impaired DNA syn
--B12 or folate deficiency
--chemotherapeutic agents
--alcoholism
What are some causes of normocytic anemia?
--deficient erythropoietin
--hemorrhage
What's the word for a high RDW?
anisocytosis (large range in size of cells)
What is considered to be a low hemoglobin content for RBCs?
hypochromic: low: MCH < 27 pg/RBC, or MCHC < 30%
Where in the intestine is iron absorbed?
duodenum and upper jejunum
What form of iron is most easily absorbed?
heme form, from animal products (we have a special intestinal transporter)
What vitamin assists iron absorbtion?
vit C
What are the storage forms of iron?
ferritin (liver, marrow, spleen, RBCs, serum)
hemosiderin (liver, marrow)
What is the most common anemia?
IDA
How much iron is required daily?
25 mg
How much of this iron is acquired by recycling?
97% (normally)
What do you expect in the CBC of someone with IDA?
serum iron and/or ferritin: low
TIBC (total iron binding capacity): high
HGB, HCT, RBC, MCV: low
RDW: high in later stages
What's the usual tx for IDA?
iron supplementation and optimization of absorbtion, monitor ferritin
With treatment, how quickly should HGB rise?
1 gram%/mo
Where is IDA most common?
in developing countries with vegetarian diet
What are some causes of impaired absorbtion of iron?
celiac dz and sprue, other steatorrhea, chronic diarrhea, gastrectomy, diet
What are some dietary substances that inhibit the absorbtion of nonheme iron?
phytates (grains, soy, nut hulls)
tanmate (skins & fruit of plants)
phosphates
Who is at the highest risk of IDA?
poor women with multiple, frequent pregnancies
What are the common causes of chronic blood loss?
GI: PUD, gastritis, carcinoma, hemorrhoids, parasites
GU: renal, pelvic or bladder tumors
Gyn: menorrhagia, AUB, uterine carcinoma
What is sideroblastic anemia?
--inadequate/abnormal utilization of marrow iron (thalassemias esp)
--usu microcytic hypochromic (mb normochormic) with high RDW
--market anisocytosis w/ siderocytes
--high serum iron, transferring & ferritin
--Dx: ringed sideroblasts, erythroid hyperplasia in bone marrow
--if cause unknown check serum lead
What does a siderocyte look like?
polychromatophilic, stippled, targeted RBC
What is anemia of chronic disease?
--aka iron-reutilization anemia
--2nd most common form of anemia
--ETIO: inflam, cancer, infx: shortened RBC life, poor Fe metabolism, deficient erythropoiesis (exact mech: unknown)
--initial normo-normo-->micro/normo or micro/hypo
--if IDA also: low serum iron and low TIBC
What is hypoproliferative anemia?
--lack of EPO or marrow malfx
--ETIO: renal dz, hypo metabolic, endocrine deficiency, protein malnutrit
--LABS: renal fx, CBC
What is aplastic anemia, aka hypoplastic anemia?
--decrease in bone marrow mass-->pancytopenia or pure RBC aplasia
--ETIO: 1/2 ideopathic (young adults), 1/2 dt: chems, drugs, benzene, chemo, age, Fanconi's (genetic w/ microcephaly and dark pigmentation)
--ETIO for pure RBC aplasia: infx, thymoma, immune sys injury, fertilizer, B2 deficient, CLL
--LABS: low RBC, WBC, PLT, Retic, high serum Fe, acellular bone marrow
What is MYELOPHTHISIC ANEMIA?
--when marrow is replace by tumor, grunloma, lipid storage or fibrosis
--may see splenomegaly
--look for nucleated RBC's in PB, also immature myeloid cells (bands)
What can cause macrocytic anemia?
--B12/folate deficiency, cytotoxic drugs-->defective DNA syn w/ normal RNA synthesis-->cytoplasm grows but nuc doesn't
--Dx: MCV > 95-100, aniso, poik, high RDW, Howell Jolly bodies
--hypersegs-->neutropenia
Why may person with B12 deficient macrocytic anemia NOT respond to B12 supplementation?
they can't absorb it because they don't have gastric parietal cells or intrinsic factor, due to autoimmune destruction of those cells
switching to pathology notes
What are some of the anemias of diminished erythropoiesis?
--megaloblastic dt B12 or folate deficiency
--IDA
--ACD
--anemia of renal failure
--marrow stem cell failure (aplastic and pure red cell aplasia anemias)
Besides B12/folate, what are some possible causes of megaloblastic/macrocytic anemias?
--hyperthyroidism
--pregnancy
--disseminated cancer (dt increased requirement)
What are two common causes of B12/folate deficiency?
vegan diet and alcoholism
What do the neutrophils look like in megaloblastic anemia?
hypersegmented nuclei in neuts and eos
How does the bone marrow appear?
markedly hypercellular dt increased numbers of all myeloid precursors
What enzyme is impaired by cobalamin/folate deficiency?
thymidine synthase--/-->DNA synthesis
What causes the asynchrony between nuclear and cytoplasmic development in megaloblastic a?
RNA synthesis is not affected so the cytoplam gets large while the nucleus stays small
What are the two disorders that result in extravascular hemolysis?
sickle cell anemia and hereditary spherocytosis (HS), because the spleen takes the oddball cells apart
What are three challenges that result in intravascular hemolysis?
1) mechanical trauma (mech heart valves, physical trauma {marathon running, bongo drumming}, malignant HTN)
2) antibody fixation (mismatched blood transfusion)
3) toxic injury to RBC's (malaria, septic shock-->disseminated intravascular coagulopathy )
What are some extrinsic causes of hemolytic anemia?
--RBC trauma dt cardiac prostheses or narrowing/obstruction of microvasculature (DIC)
--SLE, malignant HTN, TTP, hemolytic uremic syndrome (HUS), cancer
What are the two conditions that cause major clinical problems assoc w/ hemolysis?
TTP and HUS
What is TTP?
thrombocytic thrombocytopenic purpura = a rare life-threatening dz involving embolism and thrombosis of small BVs in the brain, characterized by platelet microthrombi, thrombocytopenia, hemolytic anemia, fever, renal abnormalities and neurologic changes: aphasia, blindness, convulsions, mortality w/ tx 10-20%, can be precipitated by antiplatelet drug clopidogrel (Plavix)
Extrinsic hemolytic anemia may be caused by what?
--heart valve prosthesis and A-V shunts
--infx: malaria
--chem: lead
--hypersplenism
--acquired: autoimmune, usu IgG opsonizing RBC membrane, increases splenic filtering
What are some common underlying diseases that may trigger autoimmune rxns to RBCs?
--lymphoma, carcinoma, sarcoidosis, collagen vascular dz (SLE or RA)
What conditions trigger sickle formation in sickle cell anemia?
--low pH-->low oxygen tension and HGB has lower affinity for O2-->HGB stacks up in cell
--also intracellular dehydration increases MCHC and facilitates sickling
Is the sickling of a RBC reversible?
intially, yes, but later the RBC is permanently deformed
About how long do sickle cells live in the circ?
--20 days
What fraction of American blacks carry one gene for Hb S (sickle cell disease)?
--8%, and heterozygotes have ~60% normal hemoglobin and are usually asymptomatic, or have painless hematuria, or symptoms at very high altitudes or after market exertion
What fraction of American blacks are homozygous and develop sickle cell anemia?
1/500
In Africa how many are homozygous and have the disease?
1/100
What is HbSC?
Hemoglobin C is also found more in blacks and has a greater tendency to form aggregates with deoxygenated HbS and HbA => HbSC disease. 2-3% of US blacks are asymptomatic heterozygotes. About 1/1250 has HbSC dz.
What are some S/Sx of HbS disease or anemia?
--hematuria
--retinal hemorrhages, infarctions
--aseptic necrosis of femoral head
--leg ulcers
--priapism
--painful bone infarctions
--"chest syndrome" incl: chest pain, fever, leukocytosis, lung infiltrates, possible pulmonary infarction
--"pain crisis" = vaso-occlusive crisis = bone ischemia and infarction
--sequestration crisis = spleen sequesters RBC's-->enlarges acutely-->hypovolemia and shock
--aplastic crisis = suppression of BM dt infx by Parvo B19 virus
What other blood disease decreases Sickle cell symptoms when a pt has both?
--alpha thalassemia, because the lower globin synthesis reduces the MCHC
What are some of the effects of sickle cell anemia?
--chronic hemolysis (I would guess both intra- and extra- vascular)
--more bilirubin formed
--small vessel stasis and thrombosis (ischemia of extremities)
--hyperplastic bone marrow: prominent cheekbones and changes in skull to increase marrow
--splenic changes: enlargement at first but later shrinkage dt hypoxia, thrombosis, infarction-->fibrosis-->autosplenectomy
--pigmented gallstones dt breakdown of HGB and hyperbilirubinism
What does the loss of spleen function cause?
incaresing susceptibility to ENCAPSULATED ORGANISMS such as Streptococcus, Haemophilus influenza, and Salmonella
Why is pneumovax given to sickle cell pts before the spleen is damaged? (vaccines)
--to reduce pneumococcal pneumonia and salmonella osteomyelitis-->avascular necrosis
--to develop immune response to encapsulated microorgs proactively
What are some treatments for sickle cell anemia?
--EPO (increase RBC production-->decrease anemia) long term effects unknonw
--butyrate "appears" to diminish sickling
--studies ongoing on the use of L-arginine or Sildenafil (viagra) as vasodilators
--another novel approach: hydroxyurea, chem agent that disrupts DNA replication
What are the three mechanisms by which hydroxyurea helps sickle cell anemia?
1) anti-inflam: inhibits prod of WBCs
2) increases mean RBC volume (MCV) and decreases concentration of HbS
3) can be oxidized by heme groups to produce NO (vasodilator)
--converts some of the Hgb S to Hgb F, when Hgb F reaches 10-15% there is less incidence of vaso-occlusive complications
About half of all sickle cell patients live to be how old?
50+
What are the usual causes of death?
--overwhelming infx
--pulmonary emboli
--renal failure
What might be the only sign that a person has Hb C trait?
target cells
If a person with Hb CC disease (they're homozygous), what symptoms do you expect?
--anemia
--abdominal pain
--arthralgias
--mild jaundice
--splenic enlargement but no infarcts
What kind of hemoglobin is the 3rd most common form worldwide, and is found in SE Asians?
Hgb E (Hgb AE heterozygotes are asx, Hgb EE homozygotes exhibit mild microcytic anemia and target cells)
What's the classic example of RBC membrane defect makes RBC's less deformable in the vasculature, and increases its vulnerability to splenic sequestration and destruction?
--hereditary spherocytosis
What population is most affected by autosomal dominant HS (75% of cases)?
northern Europeans, 1/5000, usu a defect in ankyrin, protein that anchors cytoskeleton
What are the three characteristic clinical features of HS?
--anemia
--splenomegaly
--jaundice
(dz is highly variable in severity, some pts may suffer aplastic crisis dt parvovirus (B19) and show slapped cheeks or lacy rash on body)
What other S/Sx may been seen in pts with HS?
--gallstones (40-50%)
What is the more severe form of HS?
the autosomal recessive variant
What is one treatment for HS that reduces extravascular hemolysis and reduces anemia?
splenectomy. the SE's may exclude this option, stand by.
What is the enzyme in the hexose monophosophate shunt that generates reduced glutathione to protect hemoglobin and RBC membranes from oxidation?
Glucose-6-Dehydrogenase
What food can cause hemolysis by generating oxidants that react with the RBC membrane?
fava beans
When an RBC is oxidatively damaged, denatured and precipitated hemoglobin can be seen as dark blue inclusion bodies. What are they called?
Heinz bodies, use crystal violet or methylene blue stain
What infections can also induce hemolysis in a person with G6PD?
viral hepatitis, pneumonia, typhoid fever
What are some drugs that do the same?
sulfonamides, antimalarials, nitrofurantoins
What is favism?
hemolysis in G6PD pt dt ingestion of fava beans, a component of which oxidizes older RBC membranes
Where is favism endemic?
Middle East, Mediterannean and parts of Africa (could this be simply because those are the regions where fava beans are eaten, and G6PD occurence is more universal??)
Why is hemolytic anemia in those with G6PD usually mild and self-limiting?
because only the older RBC's fail
What is the most common cause of thalassemia?
a defect in the production of beta globin protein-->beta thalassemia
How is alpha thalassemia different, aside from the different globin in question?
the alpha globin gene is missing, not defective
What population has the lion's share of beta thalassemia genes?
Mediterraneans
What's the difference between thalassemia trait and thalassemia major?
homozygous vs heterozygous
What kind of anemia is caused by thalassemia?
globin deficiency-->not enough HGB-->hypochromic and microcytic, mb increased RBC numbers
At what age do symptoms of beta thal major arise, and why?
5-6 months, because that's when fetal hemoglobin is no longer produced
What's the treatment and the side effect for beta thal major?
repeated transfusions-->increased iron load-->risk of hemochromatosis treated by iron chelation
Why are skeletal deformities created by untreated beta thal major?
tissue anoxia-->kidneys increase EPO output-->marrow expansion: heavy brow
If a pt with beta thal major gets transfusions and survives past childhood, what is their life expectancy?
rare to survive past 3rd decade
What happens to the free alpha globin chains when there is a beta chain deficit?
they form insoluble inclusions in normoblasts-->cell membrane damage-->apoptosis
How many genes code for each alpha globin chain?
four
Deletion of just one alpha globin gene results in what?
the silent carrier state
Deletion of two-->trait and three-->>?
alpha thal major Hgb H Dz
What is HbH?
a tetramer of excess beta-globin
What does HbH do?
--has high affinity for oxygen and does not deliver O2 to tissues
--is prone to oxidation-->Heinz bodies and bite cells
--causes moderate anemia
What population has most alpha thal major dz?
Asians
What do you call it when all four alpha globin genes are deleted?
hydrop fetalis-->death before birth without intrauterine tranfusions
What is AIHA?
autoimmune hemolytic anemia
How are AIHAs classified?
by characteristics of responsible antibody: warm or cold agglutination
What is the most common form of AIHA?
warm Ab Immunohemolytic anemia
What causes it?
50% ideopathic
50% dt SLE, Rx, or neoplastic dz ie: lymphoma
What is the Ab most commonly associated?
IgG
What happens in warm AIHA?
IgG's opsonized RBC's-->monocytes and spleen Fc receptors bind-->RBC membrane is busted
What may you find on abdominal PE if this process is established?
splenomegaly (65%)
What Ab is associated with COLD AIHA?
IgM; RBCs agglutinate at low temps 0-4 degrees C
When to the cold Ab's appear acutely?
during the recovery phase of infectious dz: mycoplasma pneumo, mono, HIV, CMV, influenza
What conditions can cause CHRONIC cold AIHA?
certain lymphoid neoplasms, and ideopathic
What's a visible sign of possible cold AIHA?
Raynaud's
What is pernicious anemia?
chronic dz dt impaired absorbtion of B12 dt lack of intrinsic factor in gastic secretions
What is cobalamin?
vitamin B12
What populations are most likely to have the adult form of pernicious anemia?
Celts and Scandinavians (10-12/100,000)
What damages the gastric mucosa eliminating IF production?
not certain, but perhaps an autoreactive T-cell response leading to Abs against parietal cells (in 90% of pts with PA but only 5% of healthy adults)
What are the 3 types of Abs found in pernicious anemia?
1) type I blocks binding of B12 to IF
2) type II prevents binding of IF-B12 complex to ileal receptor
3) type III not specific to PA but found in up to 50% of elders with chronic gastritis
What neurological complications ensue if B12 deficiency is not treated?
--myelin loss in nerves of posterior column
--megaloblastic madness: delusions, hallucinations, outbursts, paranoid schoziphrenic ideation
--in elderly: Alzheimers, memory loss, irritability, personality change
When might a pt have neurological s/sx without anemia?
taking folate or on a high folate diet but still B12 deficient
What foods contain most cobalamin (B12)?
meat and milk
Is there an association between PA and H. pylori infx?
maybe: don't know yet
Is there an association between PA and other autoimmune dz?
yes
Why did researchers postulate that people with pernicious anemia might also have H. pylori?
because they have a 2-3x risk of gastric carcinoma
PA in adults is assoc w/ gastric atrophy and achlorhydria. What nutrit deficiency follows?
iron deficiency; without acid dietary ferric is not solubized from foodstuffs
What is the gold standard of diagnosis for pernicious anemia?
endoscopic biopsy of gastric mucosa showing depleted parietal cells, gastric "intestinalization" (stomach has goblet cells like intestine)
What is an oral sign of pernicious anemia?
atrophic glossitis
What's the best way to test for B12 deficiency?
--serum < 180pg/mL (insurance pays for this test)
--more reliable, RBC levels (insurance not pay)
What other findings may indicate B12 deficiency?
increased serum homocysteine and methylmalonic acid
What are the risks associated with increased homocysteine and methymalonic a.?
atherosclerosis and thrombosis
What is pteroylmonoglutamic acid?
folate
What are dietary sources of folate?
green leafy veggies(foliage), lemons, bananas and melons, yeast and liver
What are some meds that interfere with folate absorbtion?
dilantin, oral contraceptives, phenytoin
How much folate is stored in the body?
no much: a continuous dietary supply is needed
What are some reasons for folate deficiency besides poor diet?
overcooking food, alcoholism, hx of malabsorption dz,
increased requirements: pregnancy, disseminated cancer, hemolytic anemias
What drugs impair the body's use of folate?
methotrexate (chemo)
What are serum findings in case of folate deficiency?
--megalocytes in blood (megaloblasts in marrow)
--multinucleated neuts (hypersegs)
--decreased folate level
--elevated homocysteine
What defects are found in children of women who are folate deficient during prenancy?
--neural tube defects (spina bifida)
--low birth weight
--cleft lip and palate
What bone marrow finding tells you that you have a case of IDA?
no stainable iron in mononuclear phagocytic cells
What are the 3 C's of anemia of chronic dz?
--chronic infx (osteomyelitis, bacterial endocarditis, lung abscess)
--connective tissue diseases (RA, SLE, regional enteritis (Crohn's)
--cancer: Hodgkin lymphoma, lung and breast cancer
How do you tell ACD from IDA?
ACD: low iron and TIBC but normal or elevated ferritin
IDA: low iron, high TIBC, low ferritin
How do you know if ACD is progressing?
it goes from normochromic, normocytic to hypochromic, microcytic (IDA too)
What are the main characteristics of aplastic anemia?
--peripheral pancytopenia
--marrow hypoplasia (devoid of hematopoietic elements, shows fat cells and fibrous stroma)
What is the most common way that stem cell function in aplastic anemia comes about?
activated T cells (activated by drugs, infx, envir) produce cytokines (TNF and IFNgamma) that prevent normal stem cell growth and development
What are the major causes of mortality with aplastic anemia?
infx and bleeding
What are some S/Sx of aplastic anemia?
pallor, headache, palpitations, dyspnea, fatigue, mucosal/gingival bleeding, petechial rashes, netropenia-->infx, ulcers in mouth/pharynx
What fraction of aplastic anemia is from congenital causes?
20%
What are some of the causes of acquired aplastic anemia?
infx: hepatitis, EBC, HIV, parvovirus, mycobacterium
toxins: radiation
RBC count, hematocrit, or hemoglobin content of RBC's
know anemia from CBC:
RBC male < 4.5 million, female < 4.0
HCT male < 42%, female < 37%
HGB male < 14 g/dL, female < 12 (< 11 in preg female, <13 in male per Wiggin)
If the RBC, HGB or HCT is low, what do you look at next?
MCV and MCHC to see if it's microcytic hypochromic, normocytic normochromic, or macrocytic
If the MCV is low and it's micro-hypo, what do you test next?
serum iron, TIBC, ferritin, BM biopsy, HGBE (electrophoresis of HGB, also indicated by sickle cells, target cells, or nucleated RBC's)
If MCV is in normal range (80-100 fL) then what do you check next?
serum iron, TIBC, then retics, haptoglobin, Coomb's test
If the MCV is over 100 and you have a macrocytic anemia, what do you check next?
retics, serum B12 & folate
What are the three most common causes of anemia?
iron deficiency, thalassemia, and anemia of chronic dz
If there are spherocytes in the CBC differential, what tests do you order?
Coombs test (for immune mediated hemolytic anemia) and Osmotic fragility test (for HS)
If there are nucleated RBC's present, what tests do you order?
HGBE and BM biopsy
What other labs are standard to order for anemia?
(besides the CBC and peripheral blood smear eval: retic count, stool occult blood, and urinalysis (looking for bilirubin/hemolysis or bence-jones proteins/immune issue)
Why might a normal ferritin not exclude a diagnosis of iron deficiency anemia? ???
What bone tissues are responsible for cleaning up old and malfunctioning RBC's?
spleen, liver, and bone marrow phagocytes
How long do RBC's normally live and circulate?
90-120 days
What is heme degraded to when a RBC is recycled?
bilirubin
What are two variables that provoke erythroppoietin (EPO) production from the JGA of the kidneys?
decreased O2 and increased androgens
How much can the bone marrow increase RBC production over baseline?
7-8x
How much of a RBC is hemoglobin?
90%
About what % of peripheral RBC's should be RETICS (immature/just released)?
.5-1.5%
What are the three main mechanisms of anemia?
blood loss (acute or chronic), deficient erythropoiesis, and excessive hemolysis
What part of the hemoglobin complex links temporarily to oxygen molecules?
the iron of the heme group
What are some signs of bleeding?
melena = stools or vomit stained black by blood
hematochezia = bloody feces
epistaxis = nose bleed
hematemesis = vomiting blood
menorrhagia = abnormally heavy or prolonged menstruation
What are some signs of increased hemolysis?
jaundice, dark urine
What are some symptoms of low oxygen transport capacity?
pallor, fast or weak pulse, SOB, palpitations,
dizziness, fatigue, headaches, faintness or syncope
What's the nutritional difference between internal and external blood loss?
With an internal bleed, the heme can be recycled, but with an external bleed the body is reliant on iron stores to supply RBC production
What three body systems are the usual locations for chronic hemorrhage?
--GI (ulcer, colitis, cancer), gyne (excessive menses or cancer), and GU (cancer or stone)
What are some possible causes of microcytic RBCs? (MCV < 80 fL)
--altered heme or globin synthesis (thalassemia, sickle cell, porphyria)
--iron deficiency
--anemia of chronic dz (not always)
What are some causes of macrocytic RBCs? (MCV > 95 fL)
--impaired DNA syn
--B12 or folate deficiency
--chemotherapeutic agents
--alcoholism
What are some causes of normocytic anemia?
--deficient erythropoietin
--hemorrhage
What's the word for a high RDW?
anisocytosis (large range in size of cells)
What is considered to be a low hemoglobin content for RBCs?
hypochromic: low: MCH < 27 pg/RBC, or MCHC < 30%
Where in the intestine is iron absorbed?
duodenum and upper jejunum
What form of iron is most easily absorbed?
heme form, from animal products (we have a special intestinal transporter)
What vitamin assists iron absorbtion?
vit C
What are the storage forms of iron?
ferritin (liver, marrow, spleen, RBCs, serum)
hemosiderin (liver, marrow)
What is the most common anemia?
IDA
How much iron is required daily?
25 mg
How much of this iron is acquired by recycling?
97% (normally)
What do you expect in the CBC of someone with IDA?
serum iron and/or ferritin: low
TIBC (total iron binding capacity): high
HGB, HCT, RBC, MCV: low
RDW: high in later stages
What's the usual tx for IDA?
iron supplementation and optimization of absorbtion, monitor ferritin
With treatment, how quickly should HGB rise?
1 gram%/mo
Where is IDA most common?
in developing countries with vegetarian diet
What are some causes of impaired absorbtion of iron?
celiac dz and sprue, other steatorrhea, chronic diarrhea, gastrectomy, diet
What are some dietary substances that inhibit the absorbtion of nonheme iron?
phytates (grains, soy, nut hulls)
tanmate (skins & fruit of plants)
phosphates
Who is at the highest risk of IDA?
poor women with multiple, frequent pregnancies
What are the common causes of chronic blood loss?
GI: PUD, gastritis, carcinoma, hemorrhoids, parasites
GU: renal, pelvic or bladder tumors
Gyn: menorrhagia, AUB, uterine carcinoma
What is sideroblastic anemia?
--inadequate/abnormal utilization of marrow iron (thalassemias esp)
--usu microcytic hypochromic (mb normochormic) with high RDW
--market anisocytosis w/ siderocytes
--high serum iron, transferring & ferritin
--Dx: ringed sideroblasts, erythroid hyperplasia in bone marrow
--if cause unknown check serum lead
What does a siderocyte look like?
polychromatophilic, stippled, targeted RBC
What is anemia of chronic disease?
--aka iron-reutilization anemia
--2nd most common form of anemia
--ETIO: inflam, cancer, infx: shortened RBC life, poor Fe metabolism, deficient erythropoiesis (exact mech: unknown)
--initial normo-normo-->micro/normo or micro/hypo
--if IDA also: low serum iron and low TIBC
What is hypoproliferative anemia?
--lack of EPO or marrow malfx
--ETIO: renal dz, hypo metabolic, endocrine deficiency, protein malnutrit
--LABS: renal fx, CBC
What is aplastic anemia, aka hypoplastic anemia?
--decrease in bone marrow mass-->pancytopenia or pure RBC aplasia
--ETIO: 1/2 ideopathic (young adults), 1/2 dt: chems, drugs, benzene, chemo, age, Fanconi's (genetic w/ microcephaly and dark pigmentation)
--ETIO for pure RBC aplasia: infx, thymoma, immune sys injury, fertilizer, B2 deficient, CLL
--LABS: low RBC, WBC, PLT, Retic, high serum Fe, acellular bone marrow
What is MYELOPHTHISIC ANEMIA?
--when marrow is replace by tumor, grunloma, lipid storage or fibrosis
--may see splenomegaly
--look for nucleated RBC's in PB, also immature myeloid cells (bands)
What can cause macrocytic anemia?
--B12/folate deficiency, cytotoxic drugs-->defective DNA syn w/ normal RNA synthesis-->cytoplasm grows but nuc doesn't
--Dx: MCV > 95-100, aniso, poik, high RDW, Howell Jolly bodies
--hypersegs-->neutropenia
Why may person with B12 deficient macrocytic anemia NOT respond to B12 supplementation?
they can't absorb it because they don't have gastric parietal cells or intrinsic factor, due to autoimmune destruction of those cells
switching to pathology notes
What are some of the anemias of diminished erythropoiesis?
--megaloblastic dt B12 or folate deficiency
--IDA
--ACD
--anemia of renal failure
--marrow stem cell failure (aplastic and pure red cell aplasia anemias)
Besides B12/folate, what are some possible causes of megaloblastic/macrocytic anemias?
--hyperthyroidism
--pregnancy
--disseminated cancer (dt increased requirement)
What are two common causes of B12/folate deficiency?
vegan diet and alcoholism
What do the neutrophils look like in megaloblastic anemia?
hypersegmented nuclei in neuts and eos
How does the bone marrow appear?
markedly hypercellular dt increased numbers of all myeloid precursors
What enzyme is impaired by cobalamin/folate deficiency?
thymidine synthase--/-->DNA synthesis
What causes the asynchrony between nuclear and cytoplasmic development in megaloblastic a?
RNA synthesis is not affected so the cytoplam gets large while the nucleus stays small
What are the two disorders that result in extravascular hemolysis?
sickle cell anemia and hereditary spherocytosis (HS), because the spleen takes the oddball cells apart
What are three challenges that result in intravascular hemolysis?
1) mechanical trauma (mech heart valves, physical trauma {marathon running, bongo drumming}, malignant HTN)
2) antibody fixation (mismatched blood transfusion)
3) toxic injury to RBC's (malaria, septic shock-->disseminated intravascular coagulopathy )
What are some extrinsic causes of hemolytic anemia?
--RBC trauma dt cardiac prostheses or narrowing/obstruction of microvasculature (DIC)
--SLE, malignant HTN, TTP, hemolytic uremic syndrome (HUS), cancer
What are the two conditions that cause major clinical problems assoc w/ hemolysis?
TTP and HUS
What is TTP?
thrombocytic thrombocytopenic purpura = a rare life-threatening dz involving embolism and thrombosis of small BVs in the brain, characterized by platelet microthrombi, thrombocytopenia, hemolytic anemia, fever, renal abnormalities and neurologic changes: aphasia, blindness, convulsions, mortality w/ tx 10-20%, can be precipitated by antiplatelet drug clopidogrel (Plavix)
Extrinsic hemolytic anemia may be caused by what?
--heart valve prosthesis and A-V shunts
--infx: malaria
--chem: lead
--hypersplenism
--acquired: autoimmune, usu IgG opsonizing RBC membrane, increases splenic filtering
What are some common underlying diseases that may trigger autoimmune rxns to RBCs?
--lymphoma, carcinoma, sarcoidosis, collagen vascular dz (SLE or RA)
What conditions trigger sickle formation in sickle cell anemia?
--low pH-->low oxygen tension and HGB has lower affinity for O2-->HGB stacks up in cell
--also intracellular dehydration increases MCHC and facilitates sickling
Is the sickling of a RBC reversible?
intially, yes, but later the RBC is permanently deformed
About how long do sickle cells live in the circ?
--20 days
What fraction of American blacks carry one gene for Hb S (sickle cell disease)?
--8%, and heterozygotes have ~60% normal hemoglobin and are usually asymptomatic, or have painless hematuria, or symptoms at very high altitudes or after market exertion
What fraction of American blacks are homozygous and develop sickle cell anemia?
1/500
In Africa how many are homozygous and have the disease?
1/100
What is HbSC?
Hemoglobin C is also found more in blacks and has a greater tendency to form aggregates with deoxygenated HbS and HbA => HbSC disease. 2-3% of US blacks are asymptomatic heterozygotes. About 1/1250 has HbSC dz.
What are some S/Sx of HbS disease or anemia?
--hematuria
--retinal hemorrhages, infarctions
--aseptic necrosis of femoral head
--leg ulcers
--priapism
--painful bone infarctions
--"chest syndrome" incl: chest pain, fever, leukocytosis, lung infiltrates, possible pulmonary infarction
--"pain crisis" = vaso-occlusive crisis = bone ischemia and infarction
--sequestration crisis = spleen sequesters RBC's-->enlarges acutely-->hypovolemia and shock
--aplastic crisis = suppression of BM dt infx by Parvo B19 virus
What other blood disease decreases Sickle cell symptoms when a pt has both?
--alpha thalassemia, because the lower globin synthesis reduces the MCHC
What are some of the effects of sickle cell anemia?
--chronic hemolysis (I would guess both intra- and extra- vascular)
--more bilirubin formed
--small vessel stasis and thrombosis (ischemia of extremities)
--hyperplastic bone marrow: prominent cheekbones and changes in skull to increase marrow
--splenic changes: enlargement at first but later shrinkage dt hypoxia, thrombosis, infarction-->fibrosis-->autosplenectomy
--pigmented gallstones dt breakdown of HGB and hyperbilirubinism
What does the loss of spleen function cause?
incaresing susceptibility to ENCAPSULATED ORGANISMS such as Streptococcus, Haemophilus influenza, and Salmonella
Why is pneumovax given to sickle cell pts before the spleen is damaged? (vaccines)
--to reduce pneumococcal pneumonia and salmonella osteomyelitis-->avascular necrosis
--to develop immune response to encapsulated microorgs proactively
What are some treatments for sickle cell anemia?
--EPO (increase RBC production-->decrease anemia) long term effects unknonw
--butyrate "appears" to diminish sickling
--studies ongoing on the use of L-arginine or Sildenafil (viagra) as vasodilators
--another novel approach: hydroxyurea, chem agent that disrupts DNA replication
What are the three mechanisms by which hydroxyurea helps sickle cell anemia?
1) anti-inflam: inhibits prod of WBCs
2) increases mean RBC volume (MCV) and decreases concentration of HbS
3) can be oxidized by heme groups to produce NO (vasodilator)
--converts some of the Hgb S to Hgb F, when Hgb F reaches 10-15% there is less incidence of vaso-occlusive complications
About half of all sickle cell patients live to be how old?
50+
What are the usual causes of death?
--overwhelming infx
--pulmonary emboli
--renal failure
What might be the only sign that a person has Hb C trait?
target cells
If a person with Hb CC disease (they're homozygous), what symptoms do you expect?
--anemia
--abdominal pain
--arthralgias
--mild jaundice
--splenic enlargement but no infarcts
What kind of hemoglobin is the 3rd most common form worldwide, and is found in SE Asians?
Hgb E (Hgb AE heterozygotes are asx, Hgb EE homozygotes exhibit mild microcytic anemia and target cells)
What's the classic example of RBC membrane defect makes RBC's less deformable in the vasculature, and increases its vulnerability to splenic sequestration and destruction?
--hereditary spherocytosis
What population is most affected by autosomal dominant HS (75% of cases)?
northern Europeans, 1/5000, usu a defect in ankyrin, protein that anchors cytoskeleton
What are the three characteristic clinical features of HS?
--anemia
--splenomegaly
--jaundice
(dz is highly variable in severity, some pts may suffer aplastic crisis dt parvovirus (B19) and show slapped cheeks or lacy rash on body)
What other S/Sx may been seen in pts with HS?
--gallstones (40-50%)
What is the more severe form of HS?
the autosomal recessive variant
What is one treatment for HS that reduces extravascular hemolysis and reduces anemia?
splenectomy. the SE's may exclude this option, stand by.
What is the enzyme in the hexose monophosophate shunt that generates reduced glutathione to protect hemoglobin and RBC membranes from oxidation?
Glucose-6-Dehydrogenase
What food can cause hemolysis by generating oxidants that react with the RBC membrane?
fava beans
When an RBC is oxidatively damaged, denatured and precipitated hemoglobin can be seen as dark blue inclusion bodies. What are they called?
Heinz bodies, use crystal violet or methylene blue stain
What infections can also induce hemolysis in a person with G6PD?
viral hepatitis, pneumonia, typhoid fever
What are some drugs that do the same?
sulfonamides, antimalarials, nitrofurantoins
What is favism?
hemolysis in G6PD pt dt ingestion of fava beans, a component of which oxidizes older RBC membranes
Where is favism endemic?
Middle East, Mediterannean and parts of Africa (could this be simply because those are the regions where fava beans are eaten, and G6PD occurence is more universal??)
Why is hemolytic anemia in those with G6PD usually mild and self-limiting?
because only the older RBC's fail
What is the most common cause of thalassemia?
a defect in the production of beta globin protein-->beta thalassemia
How is alpha thalassemia different, aside from the different globin in question?
the alpha globin gene is missing, not defective
What population has the lion's share of beta thalassemia genes?
Mediterraneans
What's the difference between thalassemia trait and thalassemia major?
homozygous vs heterozygous
What kind of anemia is caused by thalassemia?
globin deficiency-->not enough HGB-->hypochromic and microcytic, mb increased RBC numbers
At what age do symptoms of beta thal major arise, and why?
5-6 months, because that's when fetal hemoglobin is no longer produced
What's the treatment and the side effect for beta thal major?
repeated transfusions-->increased iron load-->risk of hemochromatosis treated by iron chelation
Why are skeletal deformities created by untreated beta thal major?
tissue anoxia-->kidneys increase EPO output-->marrow expansion: heavy brow
If a pt with beta thal major gets transfusions and survives past childhood, what is their life expectancy?
rare to survive past 3rd decade
What happens to the free alpha globin chains when there is a beta chain deficit?
they form insoluble inclusions in normoblasts-->cell membrane damage-->apoptosis
How many genes code for each alpha globin chain?
four
Deletion of just one alpha globin gene results in what?
the silent carrier state
Deletion of two-->trait and three-->>?
alpha thal major Hgb H Dz
What is HbH?
a tetramer of excess beta-globin
What does HbH do?
--has high affinity for oxygen and does not deliver O2 to tissues
--is prone to oxidation-->Heinz bodies and bite cells
--causes moderate anemia
What population has most alpha thal major dz?
Asians
What do you call it when all four alpha globin genes are deleted?
hydrop fetalis-->death before birth without intrauterine tranfusions
What is AIHA?
autoimmune hemolytic anemia
How are AIHAs classified?
by characteristics of responsible antibody: warm or cold agglutination
What is the most common form of AIHA?
warm Ab Immunohemolytic anemia
What causes it?
50% ideopathic
50% dt SLE, Rx, or neoplastic dz ie: lymphoma
What is the Ab most commonly associated?
IgG
What happens in warm AIHA?
IgG's opsonized RBC's-->monocytes and spleen Fc receptors bind-->RBC membrane is busted
What may you find on abdominal PE if this process is established?
splenomegaly (65%)
What Ab is associated with COLD AIHA?
IgM; RBCs agglutinate at low temps 0-4 degrees C
When to the cold Ab's appear acutely?
during the recovery phase of infectious dz: mycoplasma pneumo, mono, HIV, CMV, influenza
What conditions can cause CHRONIC cold AIHA?
certain lymphoid neoplasms, and ideopathic
What's a visible sign of possible cold AIHA?
Raynaud's
What is pernicious anemia?
chronic dz dt impaired absorbtion of B12 dt lack of intrinsic factor in gastic secretions
What is cobalamin?
vitamin B12
What populations are most likely to have the adult form of pernicious anemia?
Celts and Scandinavians (10-12/100,000)
What damages the gastric mucosa eliminating IF production?
not certain, but perhaps an autoreactive T-cell response leading to Abs against parietal cells (in 90% of pts with PA but only 5% of healthy adults)
What are the 3 types of Abs found in pernicious anemia?
1) type I blocks binding of B12 to IF
2) type II prevents binding of IF-B12 complex to ileal receptor
3) type III not specific to PA but found in up to 50% of elders with chronic gastritis
What neurological complications ensue if B12 deficiency is not treated?
--myelin loss in nerves of posterior column
--megaloblastic madness: delusions, hallucinations, outbursts, paranoid schoziphrenic ideation
--in elderly: Alzheimers, memory loss, irritability, personality change
When might a pt have neurological s/sx without anemia?
taking folate or on a high folate diet but still B12 deficient
What foods contain most cobalamin (B12)?
meat and milk
Is there an association between PA and H. pylori infx?
maybe: don't know yet
Is there an association between PA and other autoimmune dz?
yes
Why did researchers postulate that people with pernicious anemia might also have H. pylori?
because they have a 2-3x risk of gastric carcinoma
PA in adults is assoc w/ gastric atrophy and achlorhydria. What nutrit deficiency follows?
iron deficiency; without acid dietary ferric is not solubized from foodstuffs
What is the gold standard of diagnosis for pernicious anemia?
endoscopic biopsy of gastric mucosa showing depleted parietal cells, gastric "intestinalization" (stomach has goblet cells like intestine)
What is an oral sign of pernicious anemia?
atrophic glossitis
What's the best way to test for B12 deficiency?
--serum < 180pg/mL (insurance pays for this test)
--more reliable, RBC levels (insurance not pay)
What other findings may indicate B12 deficiency?
increased serum homocysteine and methylmalonic acid
What are the risks associated with increased homocysteine and methymalonic a.?
atherosclerosis and thrombosis
What is pteroylmonoglutamic acid?
folate
What are dietary sources of folate?
green leafy veggies(foliage), lemons, bananas and melons, yeast and liver
What are some meds that interfere with folate absorbtion?
dilantin, oral contraceptives, phenytoin
How much folate is stored in the body?
no much: a continuous dietary supply is needed
What are some reasons for folate deficiency besides poor diet?
overcooking food, alcoholism, hx of malabsorption dz,
increased requirements: pregnancy, disseminated cancer, hemolytic anemias
What drugs impair the body's use of folate?
methotrexate (chemo)
What are serum findings in case of folate deficiency?
--megalocytes in blood (megaloblasts in marrow)
--multinucleated neuts (hypersegs)
--decreased folate level
--elevated homocysteine
What defects are found in children of women who are folate deficient during prenancy?
--neural tube defects (spina bifida)
--low birth weight
--cleft lip and palate
What bone marrow finding tells you that you have a case of IDA?
no stainable iron in mononuclear phagocytic cells
What are the 3 C's of anemia of chronic dz?
--chronic infx (osteomyelitis, bacterial endocarditis, lung abscess)
--connective tissue diseases (RA, SLE, regional enteritis (Crohn's)
--cancer: Hodgkin lymphoma, lung and breast cancer
How do you tell ACD from IDA?
ACD: low iron and TIBC but normal or elevated ferritin
IDA: low iron, high TIBC, low ferritin
How do you know if ACD is progressing?
it goes from normochromic, normocytic to hypochromic, microcytic (IDA too)
What are the main characteristics of aplastic anemia?
--peripheral pancytopenia
--marrow hypoplasia (devoid of hematopoietic elements, shows fat cells and fibrous stroma)
What is the most common way that stem cell function in aplastic anemia comes about?
activated T cells (activated by drugs, infx, envir) produce cytokines (TNF and IFNgamma) that prevent normal stem cell growth and development
What are the major causes of mortality with aplastic anemia?
infx and bleeding
What are some S/Sx of aplastic anemia?
pallor, headache, palpitations, dyspnea, fatigue, mucosal/gingival bleeding, petechial rashes, netropenia-->infx, ulcers in mouth/pharynx
What fraction of aplastic anemia is from congenital causes?
20%
What are some of the causes of acquired aplastic anemia?
infx: hepatitis, EBC, HIV, parvovirus, mycobacterium
toxins: radiation