The rest of the objectives

How does lead poisening alter the heme biosynthesis pathway?

• ALA dehydratase → inhibited

  • normally converts ALA → porphobilinogen

  • causes ↑ ALA

• Ferrochelatase → inhibited

  • normally inserts Fe2+ into protophorphyrin IX → heme

  • inhibition causes ↓ heme production and ↑ protoporphyrin IX

What happens when lead poisening inhibits the heme biosynthesis pathway?

• ferrochelatase is inhibited → zinc may be inserted into protoporphyrin instead of iron → zinc protoporphyrin

• lead inhibits ALA dehydratase + ferrochelatase → ↓ heme + ↑ ALA + ↑ ZPP/protoporphyrin

What are Erythropoietic Protoporphyrins?

• porphyrin compounds that accumulate in developing RBC when heme synthesis is impaired

• when iron CANNOT be incorporated into protoporphyrin IX

What is the etiology of Erythropoietic Protoporphyrins?

• iron deficiency → insufficient iron is available to insert into protoporphyrin IX to form heme

• lead poisoning → lead inhibits enzymes in heme synthesis

• Sideroblastic anemia → defective heme synthesis → porphyrin accumulation

What do these lab findings indicate?

↓ serum iron, ferritin

↑ TIBC, RDW

microcytic / hypochromic

Erythropoietic Protoporphyrins caused by Iron deficiency

What do these labs indicate?

↑ blood lead level, basophilic stippling

↑ EP / ZPP

Erythropoietic Protoporphyrins caused by Iron deficiency

What disorders exhibit ineffective erythropoiesis?

• sideroblastic anemia

• Megaloblastic anemia

  • vitamin B12 deficiency

  • folate deficiency

• Thalassemia

• Secondary Hemochromatosis

What is Macrocytosis?

• RBC are larger than normal

What happens in megaloblastic anemia?

• issue is impaired DNA synthesis due to vitamin B12 or folate deficiency

• = DNA problem → cant divide → cell gets bigger

• ↑ MCV

• cytoplasmic growth continues while nuclear division is delayed

  • created abnormally larger erythroid cells in bone marrow

How is macrocytosis associated with megaloblastic anemia?

• B12/folate deficiency → impaired DNA synthesis → nucleus can NOT divide → RBC precursors take longr to maure → cells continue growing → larger RBC precusor → large mature RBC

What is aplastic anemia?

• bone marrow failure disorder

  • destruction of hematopoietic stem cells

  • ineffective hematopoiesis

  • destruction of BM microenvironment

  • BM cellularity < 25%

What can cause Secondary Aplastic Anemia?

• drugs

• radiation

• infection

• viruses

• chemicals

• pregnancy

• SLE

• transplants

What symptoms are associated with aplastic anemia?

• slow, asymptomatic onset

• pallow, fatigue

• tachycardia

• hypotension

• cardiac failure

• bleeding manifestations

  • petechiae , bruising

What bone marrow findings indicate aplastic anemia?

• marked hypocellular BM aspiration

• ↓ myeloid progenitors, erythroid progenitors, megakoytic progenitors

• fatty replacement of hematopoietic tissue

• BM cellularity < 25%

What is used to treat Aplastic Anemia?

• Untreated: fatal

• BM transplant

• Immunosuppressive therapy

What do these labs indicate?

pancytopenia

low Hgb (< 7.0 g/dL)

MCV / MCHC normal

retics decreased < 1%

normal morphology

↑ serum iron / % transferrin

↑ lymphocytes

ANC decreased

• Aplastic Anemia

What is the etiology of Fanconis anemia?

• inherited form of aplastic anemia

• associated with chromosome / DNA repair disorder

  • breakage of DNA crosslinking agents

  • faulty DNA repair → chromosome breakage → BM failure

What do these indicate?

• pancytopenia

• reticulocytopenia

• hypocellular BM

• macrocytic RBCs

• Fanconis anemia

What treatment is used for Fanconis anemia?

• stem cell transplant

  • sucess with sibling donors

What clinical findings can indicate Faconi anemia?

• physical malformation at birth in 2/3 of patients

• radial hypoplasia, microcephaly, hip dislocation

• hyperpigmentation / hypopigmentation

• short stature

• cross-eyed

• low birth weight

• symptoms: 5 - 10 yrs old

What can happen with Faconi anemia?

• over 90% develop BM failure by 40 yrs old

• 25% develop sold tumors

• 1/3 transition to MDS or AML

• increased risk of vulvar, esophageal, head / neck cancer

• increased telomere shortenings

What is pancytopenia?

• decreased number of ALL three major blood cell lines

  • ↓ RBC → anemia < 4.7 - 6.1 × 10^6 ul

  • ↓ WBC → leukopenia: < 4.5 -11.0 × 10³ /ul

  • ↓ PLTs → thrombocytopenia: < 150-450 × 10^9

How is chromosomal breakage associated with Fanconi anemia?

faulty DNA repair → chromosomes become unstable → chromosome breakage

• abnormal chromosomes are susceptible to DNA cross linking agents (mitomycin C)

• inherited DNA repair defect + chromosome breakage + aplastic anemia

What occurs in a Class I G6PD deficiency?

• < 10% enzyme deficiency

• chronic hemolytic anemia

What occurs in a Class II G6PD deficiency?

• severe enzyme deficiency

• intermittent acute hemolysis

What occurs in a Class III G6PD deficiency

• 10-60% enzymatic activity

• intermittent acute hemolysis

What occurs in a Class IV G6PD deficiency

• no deficiency or hemolysis

What occurs in a Class V G6PD deficiency

• increased enzymatic activity

How are fava beans associated with a G6PD deficiency?

• they trigger hemolysis in individuals with the deficiency

• fava beans → vicine + convicine → divicine → oxidative stress → RBC damage → hemolysis

What can happen if someone with a G6PD deficiency eats fava beans?

• G6PD + oxidative stress from fava beans → hemolytic episode

• individuals may be asymptomatic until exposed to trigger

• class I would be most sensitive

What are examples of Hereditary Nonspherocytic Hemolytic Anemias?

• G6PD deficiency

• PK deficiency

What is a G6PD deficiency?

• major problem: oxidative damage to RBCs

• RBCs can NOT produce enough NADPH to keep glutathione reduced

• without reduced glutathione → RBC can NOT detoxify H2O2

• leads to: hemoglobin oxidation / RBC destruction

What morphology would this disease indicate?

• normocytic / normochromic anemia

• reticulocytosis

• anisocytosis

• poikilocytosis

• spherocytosis

• schistocytes

• Helmet cells

• Heinz bodies → due to denatured Hgb

• GP6D deficiency

Here are your clinical findings. What is this

• hemoglobinuria and jaundice

• anemia

• hyperbilirubinemia (neonatal)

  • Kernicterus > 18

  • brain damage > 25

• ↑ LDH

• dark urine

• splenomegaly

• fever,chills, headache, nausea, vomiting, back/abdominal pain

• asymptomatic till exposed to triggering mechanism

• GP6D deficiency

What can trigger the symptoms of a G6PD deficiency?

• Drugs

  • Dapsone (anti-bacterial)

  • Methylene blue

  • Nitrofurantoin (anti-bacterial)

  • Phenazopyridine (urinary tract med)

  • Primaquine (anti-malarial)

• infection

• fava beans

What is used to treat G6PD deficiency?

• Discontinue implicated drugs

• RBC transfusion

What is a Pyruvate Kinase (PK) deficiency

• causes an ATP deficiency because PK is needed for glycolysis

• ↓ PK → ↓ ATP → RBC become rigid → RBC can not change shape properly

• autosomal recessive mutation in PKLR gene

• incest

What can these clinical findings indicate?

• severe neonatal anemia

• anemia

• jaundice

• splenomegaly

• gallstones

• PK deficiency

Here are your lab findings:

• normocytic / normochromic

• reticulocytosis

• anisocytosis

• poikilocytosis

• ↑ bilirubin / LDH

• ↓ haptoglobin

• normal osmotic fragility

• DAT neg

• PK deficiency

What is used to treat a PK deficiency?

• supportive RBC transfusions

• splenectomy

What is Paroxysmal Nocturnal Hemoglobinuria (PNH)?

• results from stem cell mutation → lack of GPI proteins

  • CD55

  • CD59

• these are normally protective → protect RBC from complement

Describe the pathophysiology of PNH.

1. stem cell mutation → loss of GPI anchor → loss of CD55 / CD59

2. RBC become susceptible to complement mediated destruction

3. intravascular hemolysis

4. hemoglobin released into plasma/urine

5. abnormal stem cells can affect: RBC, WBC, and PLTs

How is malaria identified in the hematology laboratory?

• peripheral blood smears for Plasmodium parasites inside RBC

What are characteristics of a Thick Blood Film?

• uses a large drop of blood

• determines: whether malaria parasites are present

• more sensitive for detecting parasites due to large blood volume

• stain: Giemsa or Wright’s Stain

  • fixed with methyl alcohol

What are characteristics of a Thin Blood Film?

• used for: species ID

• allow to examine morphology o the parasite and infected RBC

• determines: percent parasitemia

• count the number of parasitized RBC among approx: 500 - 2,000 RBC → convert to %

What specimen can be used to identify malaria?

• blood from venipuncture → EDTA

• fingerstick

Describe Plasmodium vivax.

• invades: reticulocytes

• ring form , trophozoites, infected RBC become large

Describe Plasmodium falciparum

• invades: all RBC stages

• crescent / banana shaped gametocytes

Describe Plasmodium ovale

• invades: reticulocytes

• oval shaped RBC / trophozoites

Describe Plasmodium malariae.

invades: mature RBC

older/mature RBC , characteristic band form

What is this showing?

• P . ovale trophozoites in a thin smear

What is this showing?

• P. falciparum crescent shaped gametocyte in thin smear

What is this showing?

• P. vivax ring form trophozoite

What are these examples of?

• P. falciparum

What are these examples of

• P. vivax

What are these examples of

• P. malariae

What are these examples of?

• P. ovale

What is this?

• P vivax ring form

What type of parasite is associated with cerebral malaria?

• P. falciparum

How is P. falciparum associated with cerebral malaria?

• it can infect RBC of all ages → high parasitemia

  • thats why its so dangerous

  • infected RBC can sequester in small blood vessels in brain → cerebral malaria

What values indicate Microcytic anemia?

MCV < 80

MCHC < 32

What are examples of Microcytic Anemia?

• Thalassemia - normal iron

• Iron deficiency - low iron

• Chronic disease

• Sideroblastic anemia - high iron

• Lead poisening

What are examples of Microcytic Hypochromic Anemias?

• due to deficiency of iron / abnormal iron utilization

  • thalassemia

  • iron deficiency anemia

  • sideroblastic anemia

What values indicate Normocytic anemia?

• MCV: 80 - 100

• MCHC: 32 - 36

What is associated with Normocytic aemia?

• renal disease

• acute blood loss

• hemolysis

What indicates Macrocytic anemia?

• MCV > 103

What is associated with Macrocytic anmia?

• Low B12

  • pernicious anemia

  • Malnutrition

  • GI problems

• Low folate

  • folate malnutrtition

  • GI problems

  • liver disease

• Normal or High

  • myeloproliferate disease

  • liver disease

  • CDA

What is associated with Iron Deficiency Anemia?

• ↓ MCV

• ↓ MCHC

• microcytic / hypochromic

What is associated with Megaloblastic Anemia?

• ↑ MCV

• MCHC : usually normal

• Macrocytic

What is associated with Aplastic anemia?

• MCV normal

• MCHC normal

• normochromic / normocytic

What causes Babesia?

• tick transmitted disease: B. microti

• humans are accidental host

• also transmitted by transfusion of RBC from asymptomatic donors

What are symptoms of Babesia?

• 1-9 week incubation

• asymptomatic, fever, chills, headache, sweats, nausea, fatigue

• jaundice, splenomegaly, hepatomegaly

• history of tick infected area

What does this blood smear indicate

• Babesia

  • look for tetrads of merozoites

Here are your lab results, what is this?

low Hgb

↑ retic count

↓ serum haptoglobin

bilirubinemia

leukopenia

thrombocytopenia

hemoglobinuria

proteinuria

• Babesia

What is used to treat Babesia?

• clindamycin

• quinine