2nd semester Lab Dx Unit 1

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Site of iron absorption: Duodenum
Cells which regulate iron absorption: Mucosal (of duodenum)

if iron deficient iron passed to body, if not it may be sloughed back into gut
3 stages of iron deficiency disease: 1 iron dificiency without anemia (limited stores)

2 Iron limited hematopoiesis (production of microcytic cells as body runs out of iron)

3 Iron deficiency anemia
Hypocrhomic anemia: differential diagnosis (7): 1 Iron deficiency--95%

2 beta thalassemia trait

3 Sideroblastic anemia

4 Lead poisoning

5 Anemia of chronic disease

6 Alpha thalassemia

7 Hypercuprinemia
Lab Characteristics of beta thalassemia trait (3): 1 hypochromic anemia

2 iron studies normal

3 basophilic stippling
Lead poisoning lab characteristics (2): 1 hypochromic

2 coarse basophilic stippling
Peripheral smear w/ iron deficiency (5): 1 hypochromic

2 anisocytosis

3 poikiliocytosis

4 +/- target cells

5 NO basophilic stippling
Serum iron vs TIBC in Iron deficiency: Iron is low

TIBC is high
Serum iron vs TIBC in anemia of chronic disease: iron is low

TIBC is low
iron deficiency is 95% certain if Fe/TIBC is?: < 10%
if Fe/TIBC 10-30%, then: iron deficiency must be distinguished from anemia of chronic disease
If ferritin <10, then: iron deficiency
If ferritin 10-30, then: possible iron deficiency
Clinical features of iron deficiency (4): 1 Pallor, conjunctival pallor (not specific--signs of anemia)

2 koilonychias (spoon nails)

3 angular chelosis

4 glossitis
Treatment of iron deficiency: Ferrous sulfate 300 mg t.i.d.

--60 mg of elemental iron per pill

--NO enteric coated iron
Duration of iron deficiency treatment: until hematocrit is normal, then 3-6 months to replete marrow stores
Treatment of iron deficiency with malabsorptive patients: IM injection (not IV) of iron
Conditions with decreased soluble transferrin receptor: conditions of erythroid hypoplasia, such as aplastic anemia and red cell aplasia

anemia of chronic disease
conditions with increased soluble transferrin receptor: conditions of erythroid hyperplasia, such as chronic hemolytic anemia

in iron deficiency
soluble transferrin receptor use for differential of iron deficiency and anemia of chronic disease: increased in iron deficiency

decreased in anemia of chronic disease

--useful when iron, TIBC, and ferritin are borderline
soluble transferrin receptor/log ferritin in iron deficiency vs anemia of chronic disease (#?): iron deficiency: >4

anemia of chronic disease: <1
screening test for hemochromatosis: transferrin saturation

NOTE: high saturation will be seen in aplastic anemia b/c of inability to use iron
Mutations associated with hemochromatosis: C282Y, H63D, S65C

NOTE: C282Y +/+ confirms dx
definition of megaloblastic: increase in early erythroblasts in the bone marrow
most common causes of macrocytic anemia: folate deficiency and B-12 deficiency

NOTE: these two are also megaloblastic b/c they cause slow DNA production and therefore slow maturation
Folate role in DNA synthesis: methyl donor in thymidine synthesis
Where is folate absorbed: the jejunum
folate body stores vs B12 body stores duration: folate lasts few months, B12 for 3 years

Thus, if diet interupted folate defiency first
Drug which causes folate malabsorption: dilantin (aka phenytoin), anti seizure drug
Conditions of increased folate need: pregnancy and hemolytic anemia
Tests specific for folate deficiency (2): red cell folate

serum folate (not as good, since one meal may raise serum, but not red cell folate)
Blood smear and marrow in folate deficiency: smear: macrocytic with hypersegmented neutrophils

megaloblastic marrow
Therapy for folic acid deficiency: Folic acid 1 to 5 mg/day
Danger of folic acid replacement therapy w/o B12 evaluation: Blood counts may correct, but neurologic problems may progress
Role of B-12: via role in methionine synthesis, converts methyl-THF to THF
steps of B12 absorption (3): 1 stomach: binds to R factors, protects it from acid degradation.

2 Duodenum: pancreatic enzymes free B12 from R binders, binds to intrinsic factor (from parietal cells)

3 B12-IF absorbed by terminal ileum
Conditions associated with pernicious anemia (5): 1 premature gray hair

2 Vitiligo

3 Thyroid disease

4 Hypoparathyroidism

5 Gastric atrophy w/ achlorhydria
Causes of B12 deficiency Diet (1): vegan diet, no eggs, cheese, or meat
Causes of B12 deficiency Gastric (5): 1 pernicious anemia

2 Decreased IF

3 Atrophic gastritis

4 gastrectomy

5 Zollinger-Ellison (inc acid, no binding to IF)
Causes of B12 deficiency: Intestinal (4): 1 regional enteritis
2 celiac disease
3 pancreatic disease (no enzymes to liberate from R binders)
4 blind loop

--also fish tapeworm, rare
Clinical features of B12 deficiency (5): 1 pallor w/ lemon yellow skin (due to hemolysis in marrow)

2 Glossitis (beefy tongue, megaloblastic tongue)

3 paresthesia of hands and feet, position and vibration sense loss

4 combined system disease (demylenization of dorsal and lateral columns)

5 other neuro: somnolence, altered taste and smell, scotomata, dementia
Dx of b12 deficiency based on serum B12: <100 diagnostic
100-200 suspicias
>200 normal
test to establish diagnosis and pathophysiology of B12 deficiency: Schilling test

Give radioactive B12 by mouth

2 hrs later, give a flushing dose of B12 I.M. (1 mg)

measure urine radioactivity vs feces. If in urine, then it was absorbed.

Repeat with oral intrinsic factor
Therapy for B12 deficiency: 1000 micrograms/day x 2 weeks, then weekly until hematocrit is normal. Brisk reticulocytosis occurs within a week.
METHYLMALONIC ACID TEST, why?: Since B12 is required to convert methylmalonate to succinate, some physicians advocate testing for urine methylmalonic acid as a diagnostic test for B12 deficiency
MACROCYTIC ANEMIA â€“ the full differential diagnosis(8): 1 Folate and B12 deficiency are 95% or more of cases

2 Chemotherapy with antimetabolites

3 Alcohol â€“ even in the absence of folate deficiency

4 Liver disease

5 Hypothyroidism

6 Myelodysplasia (usually a normocytic anemia, can be macrocytic)

7 INCREASED RETICULOCYTES â€“ Each 1% elevation of retics raises the MCV 1 point.

8 Myeloma and dysproteinemias (artefactual). Cells clump together and the machine counts two cells as one.
Differential: anemias of bone marrow failure(6): 1 APLASTIC ANEMIA

2 PURE RED CELL APLASIA

3 MYELOFIBROSIS

4 MYELODYSPLASIA

5 MYELOPHTHISIC ANEMIA

6 ANEMIA OF CHRONIC DISEASE
Dx of aplastic anemia: bone marrow biopsy showing aplasia
tx of aplastic anemia (2): Immune therapy with anti-lymphocyte serum, cyclosporine, and cortiocosteroids

bone marrow transplant
Pure red cell aplasia dx: Low hematocrit

LOW (or zero) reticulocytes

NORMAL wbc and platelets

Marrow: NO red development, everything else normal
Two possible causes and one association of pure red cell anemia: Cases may be drug related (dilantin), or may occur post infection (with parvovirus) or in association with thymoma.
Tx of pure red cell aplasia: corticosteroids, immunosuppressive therapy

blood transfusions, iron management.

very survivable
myelofibrosis (aka agnogenic myloid metaplasia) dx: splenomegaly (can be MASSIVE)

teardrop cells on blood smear give a hint. white count usually normal--can be elevated, resembling CML

biopsy showing fibrosis is diagnostic (aspirate often "dry tap")
types of myelodysplasia with high rate of leukemia development: RAEB--refractory anemia with excess blasts

RAEB-T--refractory anemia with excess blasts in transformation
myelodysplasia dx: anemia

Pathologic sideroblasts containing more than five iron granules per cell

low reticulocyte count
MYELODYSPLASIA: group of clonal disorders, present with anemia, half of the patients eventually die of leukemia, others have marrow failure without leukemia at the time of death
MYELOPHTHISIC ANEMIA: Anemia due to bone marrow replacement usually by a tumor
Diagnosis? RBC smear: Normal Marrow: Hypoplasia WBC: Decreased Differential: Normal or decreased polys Platelets: Decreased: Aplastic Anemia
RBC smear Normal Marrow No RBCs WBC Normal Differential Normal Platelets Normal: Pure Red Cell Aplasia
RBC smear Teardrops Marrow Fibrosis WBC Variable Differential Normal or increased Myelocytes and other immature WBCs Platelets Normal or Low: Myelofibrosis
RBC smear Normal Marrow Ineffective RBC Production WBC Variable, normal or low Differential Normal, Increased blasts when advanced Platelets Normal: Decreased in advanced stages: Myelodysplasia
RBC smear Nucleated RBCs Marrow Infiltration by tumor or other process WBC Variable Differential Variable: normal or may resemble myelofibrosis (inc myelocytes and other immat. Wbc's) Platelets Decreased: Myelophtisis
RBC smear Normal Marrow Normal WBC Normal Differential Normal Platelets Normal: Anemia of Chronic Disease
drug that delays progression of myelodysplasia to acute leukemia: Vidaza
Cytogenetics more likely to be abnormal in which two myelodysplasias: RAEB (Refractory anemia with excess blasts) and RAEB-T (Refractory anemia with excess blasts in transformation)
subtypes of myelodysplastic syndrome: Refractory anemia RA
Refractory anemia with ringed sideroblasts RARS
Refractory anemia with excess blasts RAEB
Refractory anemia with excess blasts in transformation RAEB-T
Chronic myelomonocyctic leukemia CMML
most prominent feature of myelodysplastic syndromes ("often"): Anemia
cell lineages involved in myelodysplastic syndromes: Red cells, granulocytes and platelets are involved
Therapies that do not work for myelodysplasia: 13 cis retinoic acid

Corticosteroids

Androgens

Low dose cytosine arabinoside
interpretation of reticulocyte count vis a vis hemolytic anemia: increased in hemolytic anemia, does not PROVE hemolysis

Bleeding causes increased reticulocyte count

NOTE: Concommittant problem limiting red cell production (i.e. parvo virus injury of marrow) can lower rets
How do you know if anemia is hemolytic? (5): 1 Reticulocyte count is elevated

2 Bilirubin is up and unconjugated

3 LDH (lactic dyhydrogenase) will be elevated

4. HAPTOGLOBIN: down (if intravascular, not spleenic hemolysis)

5. Decreased chromium 51 survival (rarely measured)
Classes of hemolysis (where is the defect?) (4): 1 Outside the red cell (IgG "warm", IgM "cold", hypersplenism, other)

2 Membrane defects (spherocytosis)

3 Enzyme defects (90% G6Pd--oxidant sensitive; pyruvate kinase 10%)

4 Abnormal hemoglobin
Dx of immune hemolytic anemia: 1 Positive Coombs test (direct version)

2 lab determines which type of antibody or complement (IgG warm, IgM cold)
Treatment of warm antibody hemolysis (3): 1 corticosteroids. if fails..

2 splenectomy. if fails..

3 immunosuppression
Treatment of cold antibody hemolysis (3): 1 keep patient warm, blood products warm

2 Plasmapheresis (b/c IgM intravascular)

3 Cytotoxic therapy

--NO splenectomy or steroids
conditions associated with IgG hemolysis (3): 1 systemic lupus

2 chronic lymph leuk

3 lymphoma
conditions assoc with IgM hemolysis (3): 1 mycoplasma infection

2 infectious mono

3 Waldenstrom's macroglobunemia
3 mechs of drug caused hemolytic anemia: 1.Antibody against a drug which binds to the membrane when present in very high concentration â€“ occurs with high dose pencillin.

2.Neoantigen formation, the antibody is against a drug/membrane complex This is the most common mechanism of drug related hemolytic anemia

3.Aldomet mechanism. Autoimmune hemolytic anemia like idiopathic process occurs. No need for drug to be present.
chinese:spherocytosis: çƒå½¢çº¢ç»†èƒžç—‡

qiÃºxÃng hÃ³ngxÃ¬bÄo zhÃ¨ng

"spherical RedCell disease"

spherocytosis
ÙƒØ±ÙŠØ© ØÙ…Ø±Ø§Ø¡ ÙƒØ±ÙˆÙŠØ©: Red globule spherical

spherocytosis
çƒå½¢çº¢ç»†èƒžç—‡ qiÃºxÃng hÃ³ngxÃ¬bÄo zhÃ¨ng: qiúxíng hóngxìbāo zhèng

"spherical RedCell disease"

spherocytosis
spanish: spherocytosis: esfirocitosis
arabic spherocytosis: ÙƒØ±ÙŠØ© ØÙ…Ø±Ø§Ø¡ ÙƒØ±ÙˆÙŠØ©

Red globule spherical
WARM ANTIBODY hemolytic anemia 1 molecule bound to cell? 2 where macrophage binding? 3 which organ injured? 4 Injury extra or intra vasc? 5 Rx?: 1 IgG
2 Macros bind in cords of Billroth in spleen
3 Splenic destruction
4 extravascular
5 Corticosteroids, splenectomy
COLD ANTIBODY hemolytic anemia 1 molecule bound to cell? 2 where macrophage binding? 3 which organ injured? 4 Injury extra or intra vasc? 5 Rx?: 1 Complement--fixed by transient IgM
2 Liver
3 Hepatic injury
4 Intravascular
5 Keep warm, plasmapheresis, cytoxic chemotherapy
Hereditary spherocytosis most common defect: spectrin (membrane protein)
hereditary spherocytosis Rx: splenectomy
Diagnosis of Sickle cell: Hemoglobin electrophoresis â€“ mostly S, some F, some A2, no A

NOTE: If A is present it is either sickle thalassemia (S>A) or sickle trait (A>S)
è¡€çº¢è›‹ç™½ xuÃ¨hÃ³ng dÃ nbÃ¡i: xuèhóng dànbái

bloodred eggwhite (protein)

hemoglobin
screening test for sickle cell diesease or trait: sodium metabisulfite
Blood smear of thalassemia (5): 1 Microcytic anemia
2 hypochromia
3 anisocytosis
4 target cells
5 basophilic stippling

NOTE: basophilic stippling does NOT occur in Fe deficiency
Thal trait vs Fe deficiency: Iron normal, iron binding normal, Hgb A2 elevated (3.5% vs 2.5%), basophilic stippling
è‘¡è„ç³–å…ç£·é…¸é¹½è„«æ°«é…¶ç¼ºä¹ç—‡ pÃºtaotÃ¡ng liÃ¹ lÃnsuÄnyÃ¡n tuÅ qÄ«ng mÃ©i quÄ“fÃ¡-zhÃ¨ng: pÃºtaotÃ¡ng liÃ¹ lÃnsuÄnyÃ¡n tuÅ qÄ«ng mÃ©i quÄ“fÃ¡-zhÃ¨ng

grape-sugar 6 phosphorous-acid-salt break hydrogen enzyme(ferment) lack-disease

Glucose-6-phosphate dehydrogenase deficiency
ttp, who cares?: Without treatment 80% die, with treatment, plasmapheresis,

80-90% are cured.
Ø§ÙØ³Ù’ØªÙØ®Ù’Ø±Ø§Ø¬ Ø¨Ù„Ø§Ø²Ù…Ø§: plasmapheresis
è¡€æµ†å–å‡ºæ³• xuÃ¨jiÄng qÇ”chÅ« fÇŽ: xuÃ¨jiÄng qÇ”chÅ« fÇŽ

blood-syrup takeout method

plasmapheresis
Mechanism of PAROXYSMAL COLD HEMOGLOBINURIA: in cold, IgG binds to rbc's. when warm, cells lyse.
Coomb's negative for IgG, + for complement.
Cross reactivity w/ syphilis?
erythrocytosis differential: pseudoerythrocytosis--low plasma volume

secondary erythrocytosis--"reactive" to erythropoietin--could be physiologic or abnormal

polycythemia vera
abnormal causes of erythropoietin elevation (6): 1 renal disease
2 CNS disease
3 liver disease
4 cushings
5 adrenal adenoma
6 uterine fibroids
diagnostic criteria of polycythemia vera: Red cell mass (volume) Males >36 ml/kg; Females > 32 ml/kg

Oxygen saturation >92%

bone marrow with trilineage hyperplasia
3 steps of evaluation of elevated hematocrit: 1 if hematocrit >60, then not pseudoerythrocytosis. If < 60, start with red cell volume and plasma volume.

2 2ndary erythrocytosis vs. P vera. Test for common 2ndary causes (hypoxia, CO) Perform
A Complete Blood Counts
B Arterial blood gases with CO level
C Bone marrow aspiration and biopsy

3 If no diagnosis, then look for exotic causes:
Perform
A Renal ultrasound
B Pelvic and abdomen CT
C Oxygen dissociation (abnormal hemoglobin)

NOTE: phlebotomy can treat P Vera and 2ndary so not always necessary to definitively diagnose
Treatment of pseudoerythrocytosis: Volume repletion
Treatment of secondary erythrocytosis: treat underlying disorder (hypoxia, etc)
phlebotomize to hematocrit under 48
Tx of polycythemia vera: Phlebotomy <70
P32 (radioactive phosphorus) for older
A1 and A2 diagnostic criteria of polycythemia vera: A1: Raised red cell mass (volume) more than 25% above mean normal predicted value, or hematocrit > 60 in males or > 56 in females

A2: Absence of cause of secondary erythrocytosis
PURE RED CELL APLASIA: An autoimmune disease in which an antibody to early erythrocytes is present.
ANEMIA OF BONE MARROW FAILURE common lab features: 1 normocytic anemias
2 low reticulocyte count
3 crucial diagnostic test in this situation is the bone marrow aspirate/biopsy
APLASTIC ANEMIA: initially thought to represent toxic, irreversible damage to bone marrow stem cells

low hematocrit, platelet, granulocytes

immunosupression often works, so autoimmune
MYELOFIBROSIS: A clonal myeloproliferative disorder in which a stem cell exists which grows better outside the marrow, in the spleen
ANEMIA OF CHRONIC DISEASE: 1 A non-specific term used to describe those cases in which a chronic condition is associated with an anemia for which no specific cause can be found.

2 Inflammation could mute response to erythropoietin
low vs high reticulocyte count in anemic patient. MCV significance: If high hemolytic or blood loss

If low, anemia of bone marrow failure--will increase MCV
Tests for iron deficiency: 1 Peripheral smear--hypochromic w/ anisocytosis and poikilocytosis, NO basophilic stippling

2 Serum iron/serum iron binding capacity. Low for iron deficiency

3 Serum ferritin, proportional to body stores.

4 Bone marrow definitive, but $ and ivasive
most common cause of iron deficiency: Bleeding is most common cause of this anemia
what is the biochemical problem of sickle cell anemia: Amino acid substitution as 6 position of beta chain, glutamine to valine
Most common anemia(s) with following morphology: macrocytic: Morphology associated with: Folate deficiency
Most common anemia(s) with following morphology: Normocytic (w/ low reticulocytes): Morphology associated with: Pure red cell aplasia & Myelodysplasia
Most common anemia(s) with following morphology: Hypochromic: Morphology associated with: Iron deficiency
Most common anemia(s) with following morphology: microcytosis: Morphology associated with: Thalassemia
Most common anemia(s) with following morphology: Dimorphic micro and macrocytes: Morphology associated with: sideroblastic anemia
Most common anemia(s) with following morphology: Schistocytes: Morphology associated with: Microangiopathic hemolytic anemia
Most common anemia(s) with following morphology: Target cells: Morphology associated with: Iron deficiency, splenectomy, thalassemia
Most common anemia(s) with following morphology: Teardrop cells: Morphology associated with: Myelofibrosis
Morphology associated with: Folate deficiency: Most common anemia(s) with following morphology: macrocytic
Morphology associated with: Pure red cell aplasia & Myelodysplasia: Most common anemia(s) with following morphology: Normocytic (w/ low reticulocytes)
Morphology associated with: Iron deficiency: Most common anemia(s) with following morphology: Hypochromic
Morphology associated with: Thalassemia: Most common anemia(s) with following morphology: microcytosis
Morphology associated with: sideroblastic anemia: Most common anemia(s) with following morphology: Dimorphic micro and macrocytes
Morphology associated with: Microangiopathic hemolytic anemia: Most common anemia(s) with following morphology: Schistocytes
Morphology associated with: Iron deficiency, splenectomy, thalassemia: Most common anemia(s) with following morphology: Target cells
Morphology associated with: Myelofibrosis: Most common anemia(s) with following morphology: Teardrop cells

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