Final

What is Anemia

Condition of red blood cell deficiencies leading hypoxia throughout the body

Common patient symptoms of anemia

• Malaise/fatigue

• Low hemoglobin

• Shortness of breath

• Headaches

• Pale skin

• Weakness

• Increased heart rate

• Chest pain

How is anemia generally classified

By the reticulocyte count and the MCV of RBCs

Would an anemia due to blood loss or anemia due to cell pathway defects show more retics?

Anemia due to blood loss - body trying to compensate for loss and has necessary components to do so

General causes of anemia

Ineffective erythropoiesis

Insufficient erythropoiesis

Excessive blood loss

Hemolysis

What molecules can cause anemia if the body is lacking them

B12/Folate (megaloblastic anemia)

Globin chains (thalassemia)

Heme synthesis enzymes or B6 (sideroblastic anemia)

Iron (Iron deficiency anemia)

Common causes of insufficient erythropoiesis

IDA

Decreased EPO (Kidney damage)

Autoimmune diseases or infections

Replacement of normal hematopoietic cells with malignant cells

Features of acute excessive blood loss

Often occurs due to traumatic injury, body increases RBC production in days following the injury

Features of chronic excessive blood loss

Often occurs due to intermittent or internal bleeding (GI bleeds). Hard to detect and often induces IDA

Hemolytic anemia

Increased RBC destruction due to intrinsic or extrinsic defects. If bone marrow cannot compensate, this leads to anemia

General causes of intrinsic hemolytic anemias

Membranopathies, enzyme deficiencies, hemoglobinopathies

General causes of extrinsic hemolytic aneia

Antibody mediated hemolysis, mechanical injury, infection

First common tesr that is ordered to detect anemia

CBCD

What is a microcytic anemia

Low hemoglobin showing microcytic RBCs (<80 fL) and often seen with hypochromic cells (due to poor hemoglobinization)

Expected bone marrow results if anemia is caused by ineffective or insufficient erythropoiesis

Decreased M:E ratio - erythroid hyperplasia due to EPO trying to ramp up production

How does iron deficiency cause anemia

No iron is present to be incorporated into the protoporphyrin IX ring, so little amounts of heme are produced

Severe symptoms of anemia

Spooning of the nails

Sore tongue

Muscle dysfunction

Blue sclera

Pica (esp in IDA)

3 stages of iron deficiency anemia

Storage iron depletion

Storage iron pool exhaustion

Iron deficiency anemia

IDA Stage 1: Storage iron depletion

Store iron pulled for use. No symptoms and RBC production remeans

IDA Stage 2 - Storage iron/pool exhausion

Patuent Hgb starts decrease and cells begun micro/hypo due to lack of iron stores.

Iron study results in storage iron depletion

Decreased serum ferritin and Bone Marrow may show decreased amounts while serum is normal.

Iron studies of storage iron/pool exhaustion stage

Decreased iron in all areas incl bone marow

PBS appearance of storage iron/pool exhaustion

Mixed population of micro/hypo + normo/normo as the anemia is developing

CBCD and PBS appearance of Iron Deficiency Anemia

Low Hgb, decreased MCV. Microcytic and hypochromic RBCs

Bone marrow appearance of IDA

Decreased iron stores (visualized with Perl’s Prussian Blue)

Normoblasts may have ragged cytoplasm

Iron study results for IDA

Serum iron decreased

Serum ferritin decreased

TIBC increased

Transferrin saturation decreased

Typical treatment of IDA

Oral iron supplements. Severe cases = IV transfusion

4 main causes of IDA

Blood loss (menstruation, GI bleed)

Insufficient dietery intake

Reduced adsorption (Cliac, Crohn’s Gastric bypass)

Increased body requirements (pregnancy, growth spurts)

What is the main cause of sideroblastic anemia

Defect in heme production due to a decreased protoporphyrin production or inability to incorporate iron into heme

Hereditary causes of Sideroblastic anemias

Enzyme deficiencies - enzymes required in heme synthesis are lacking. Most common is ALA synthase

• Results in MDS known as refractory anemia with ringed sideroblasts

Acquired causes for Sideroblastic anemia

Lead poisoning - lead inhibits ALA dehydratase enzyme in protoporphyrin path + hinders iron incorporation into ring

Drugs - Inhibt vitamin B6, or suppress hematopoiesis and interfere with iron metabolism

CBCD + PBS appearance of sideroblastic anemia

Low Hgb, High RDW. PBS shows dimorphic population (Micro/Hypo + Normo/Normo)

Bone marrow appearance in Sideroblastic anemia

Increased iron stores (Perl’s Prussian Blue)

Ringed sideroblasts/siderocytes

Decreased porphyrins

Erythroid hyperplasia

Iron study results for Sideroblastic anemia

Serum iron increased

Serum ferritin increased

TIBC decreased

Transferritin saturation increased

What is anemia of chronic infection

A microcytic anemia associated with infections, inflammation, autoimmune diseases, and malignant neoplasms

Caues of ACI

Impaired Iron Kinetics, Impaired Erythropoiesis, Decreased RBC survival

How does impaired iron kinetics in ACI cause anemia

During chronic infection, the body removes available serum iron and stores as ferritin to prevent infectious agents for using iron. At the same time Macrophages in RES (spleen) sequester iron

How does impaired erythropoiesis in ACI cause anemia

Inflammatory cytokines during infection hinder the action of EPO on hematopoietic stem cells in bone marrow. This dampens BM response to anemia and there is a lack of compensation

How does decreased RBC survival in ACI cause anemia

In infections, the body + immune system on high alert - RBCs passing through the reticuloendothelial system are removed at a higher rate than normal

CBCD + PBS appearance of ACI

Low Hgb, decreased MCV. microcytic and hypochromic RBC

Bone marrow appearance of ACI

Normal to increased iron stores. No erythroid hyperplasia

Iron studies results of ACI

Serum iron decreased

Serum ferritin increased

TIBC decreased

Transferrin saturation is decreased to normal

How to differentiate between IDA and ACI

CRP (inflammation marker) will be high in ACI

Iron studies: Ferritin increased in ACI due to storage/sequestering, and TIBC is decreased

What is a macrocytic anemia

Anemia (low Hgb) characterized by MCV > 100 fl

How are macrocytic anemias differentiated

Megaloblastic anemias (impaired DNA synth, MCV>110, ovalocytes)

Non-megaloblastic (MCV, 100 fL, round cells)

What causes megaloblastic anemia

Impaired DNA synthesis and metabolis affect the rapidly dividing cells in the body (such as hematopoietic cells). Most common cause of this is Vitamin B12 or Folate deficiencies

What non-megaloblastic condition can cause megaloblastic changes?

Myelodysplastic syndrome

What is bone marrow nuclear:cytoplasmic asynchrony

Cytoplasm of cells in BM matures at a normal rate while nuclear maturation is delayed

Clinical presentation of patients with megaloblastic anemia

Features of anemia + jaundice. In severe cases, can cause glossitis (loss of tongue epithelium), gastritis, nausea, constipation

Severe side effects seen in B12 deficiencies

Can cause neurlogical symptoms: memory loss, numb/tingling digits, loss of balance, psychosis, hallucinations, depression

Caused by demyelination of spinal cord and nerves

Severe side effects seen in folate deficiencies

Caused increased homocysteine levels, leading to thrombosis, cardiovascular disease, and may be at risk of neurological problems such as psychosis or depression

Use of folate and B12 in DNA synthesis and maturation

Folate is converted into 5-methyl THF, and 5mTHF donates a methyl group to uracil in the presence of B12 to convert it to thymine

When Vitamin B12 and folate are missing, how do cells attempt DNA replication

Cells insert uridine into DNA in plase of thymine. During DNA proofreading, uridine is removed and leaves empy spaces = DNA strands break and replication is incomplete

Why are megaloblastic changes seen in all cell lines with B12/folate deficiencies

All cells require thymine for DNA synthesis, so all cell lines will be affected

Where is Vitamin B12 and Folate absorbed in the body

In the small intestine

Vitamin B12 route from stomach to liver

1. B12 binds to haptocorrin in stomach and is absorbed into interstitial cells found in ileum

2. Vitamin B12 is transported by transcobalamin II from the blood to the liver

How is folate brought to the liver

Folate enters intestinal cells in the jejunum through a transport protein in the cells and will be transported from the blood to the liver by proteins (albumin)

Major causes of folate deficiency

Dietary Deficiency

Malabsorption (IBD, surgery)

Increased requirement (pregnancy, children, Hemolysis, leukemia)

Impaired utilization (drugs, alcohol)

Increased loss (dialysis)

Major causes of Vitamin B12 deficiency

Dietary issues

Malabsorption (gastrectomy, IF deficiency, pancreatic disease, H.pylori infection, pernicious anemia, IBD, tapeworms)

Increased requirement (pregnancy, lactation, growth)

Transport protein defects (transcobalamin defects)

What is pernicious anemia

Autoimmune disorder that causes a lack of Intrinsic Facotr due to parietal cell destruction

Pathology behind pernicious anemia

Abnormal T4 cells destroy ATPase in parietal cells

Continuous activation of immune system leads to parietal cell destruction

What are some causes of non-megaloblastic anemia

Normal newborns

Reticulocytosis

Liver disease

Chronic alcoholism

Bone marrow failure

Post-splenectomy

How does liver disease cause non-megaloblastic anemia

Increased incorporation of cholesterol and phospholipids into to the RBC membrane

How does splenectomy cause non-megaloblastic anemia

Excess membrane is not removed from retics

CBCD and PBS findings of megaloblastic anemia

Low Hgb, Increased MCV. Oval megaloblasts, hypersegmented neutrophils

Bone marrow appearance in megaloblastic anemia

Normal to increased iron stores

Erythroid hyperplasia

Megaloblastic changes: Nuclear-cytoplasmic asynchrony, large bands/myeloid/precursor cells, increased apoptosis/Karyorrhexis, may see abnormalities in all 3 cell lines

Iron study results in megaloblastic anemia

Normal iron studies

What is aplastic anemia

Anemia characterized by Bone marrow failure and subsequent decreased hematopoietic stem cells. Causes pancytopenia

Acquired causes of aplastic anemia

Idiopathic, or secondary to toxic agent or virus exposure

Inherited causes of aplastic anemia

Fanconi’s anemia, Dyskeratosis congenita, Schwachman-Diamond syndrome

How do toxic agents or radiation cause aplastic anemia

Causes direct damage to stem cells. leads to decreased survival+ self renewal, increased apoptosis, adequate bone marrow stroma and growth factors

How does telomere shortening cause aplastic anemia

Decreased telomeres triggers apoptosis (caused by lack of telomerase complex gene or repair genes)

How does Immune-mediated destruction cause aplastic anemia

Cytotoxic T cells destory stem cells

Cytokine production suppresses hematopoiesis and induces apoptosis

What is Fanconi’s anemia

Autosomal recessive or X linked disorder that causes chromosoml fragility, causing them to be predisposed to leukemia and cancer development

What is dyskeratosis congenita

Inherited disorder that causes patients to have reduce telomerase activity, causing stem cells and proliferating cells to die sooner.

What is pure red cell dysplasia

Severe decrease of RBC precursors (other cell lines are unaffected)

Acquired pure red cell aplasia

Idiopathic or auto immune related condition causing severe normocytic anemia and reticulocytopenia. WBC and PLT counts normal

Congenital Pure Red Cell Aplasia

Mutations in specific genes effect structure of ribosome proteins and hematopoiesis transcription factors. Patients habve severe macrocytic anemia and reticulocytopenia. WBC are normal to decreased and PLT counts are normal to slightly increased

Aplastic anemia CBCD + PBS findings

Pancytopenia (low Hgb, low PLT, Low WBC), Normo/Normo or Macro RBCs

Bone Marrow appearance in aplastic anemia

Increased yellow fatty tissue, often causing a failed BM aspirate requiring a hole-punch or trephine biopsy for histo processing

Why is macrocytes seen in late stage aplastic anemia?

Ineffective erythropoiesis

Aplastic anemia treatment

Supportive therapy - transfusions, prophylactic medications while waiting for a bone marrow transplant

What is a hemolytic anemia

Disorders that shorten the RBC survival in circulation due to destruction via intravascular or extravascular hemolysis

Physiological results of hemolytic anemia

Normal responses to low oxygen levels tissue through th eincrease in EPO. This allows bone marrow to keep up with demand and compensate for the anemia

What causes intrinsic hemolytic anemias

Defects in the RBCs (membrane defects, enzyme effects, hemoglobinopathies) - can be inherited or acquired

What causes extrinsic hemolytic anemias

Acquired dects allowinf external agents to act on normal cells (immune, infections, chemicals, toxins, hypersplenism, mechanical injury)

Qualitative hemoglobinopathies

Structural defects caused by amino acid substitutions leading to Hgb variants

Quantitative hemoglobinopathies

decreased synthesis of normal globulin chains due to allele mutations

Normal protein structure of hemoglobin

4 globin chains (2 alpha and 2 beta) connect together

What causes heinz bodies

Globin chains precipating out into the cytoplasm (can be viewed using supravital stains)

Genetics of globin chains

Alpha chain encoded twice on each chromosome. Beta chain encoded once per chromosome.

Humans will have 4 alpha genes and 2 beta chains

Anemia classification of thalassemias

Start as normo/normo but then go micro/hypo

Beta thalassemia

Decrease in beta globin chain production due to a mutation of one or both genes. Altered genes produce less beta chains or none at all.

Why are heinz bodies often seen in beta thalassemia

Excess alpha chains produced precipitate out into the cell cytoplasm = Heinz bodies. These red cell inclusions lead to earlier cell death

B+ (beta +) gene

altered beta gene that results in decreased beta globin chain production

B0 (beta null) gene

Null gene - altered gene that does not produce any beta chains

beta thalassemia minor (trait) + genetics

Heterozygous condition where one normal gene is inherited with one altered or null gene:

B/B+ or B/B0

B thal major + genetics

Double heterozygous or homozygous condition where both genes are altered

B+/B+, B+/B0, or B0, B0

What happens to beta chains in alpha thalassemia

precipitate out of solution and form nonsense tetramers that are non-functional. leads to decreased life span