Heme-Pathology Flashcards
What is this and what diseases is it seen in?
Acanthocyte (aka ‘spur cell’) seen in liver disease and abetalipoproteinemia
What is abetalipoproteinemia?
a rare AR disorder that interferes with the normal absorption of fat and fat-soluble vitamins from food. It is caused by a mutation in microsomal triglyceride transfer proteinresulting in deficiencies in the apolipoproteins B-48 and B-100, which are used in the synthesis and exportation of chylomicrons and VLDL respectively.
What is this and when is it seen?
Basophilic stippling seen in lead poisoning
What is this and when is it seen?
bite cell seen in G6PD deficiency
What are these and when are they seen?
elliptocytes seen in hereditary elliptocytosis
What are these and when are they seen?
ringed sideroblasts seen in sideroblastic anemia
Describe sideroblastic anemia
In sideroblastic anemia, the body has iron available but cannot incorporate it into hemoglobin, which red blood cells need to transport oxygen efficiently. The disorder may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome, which can evolve into hematological malignancies (especially acute myelogenous leukemia).
What are the causes of sideroblastic anemia?
Congenital sideroblastic anemia.
Acquired clonal sideroblastic anemia
Acquired reversible sideroblastic anemia
Describe Congenital sideroblastic anemia
X-linked sideroblastic anemia: This is the most common congenital cause of sideroblastic anemia and involves a defect in ALAS2, which is involved in the first step of heme synthesis. Although X-linked, approximately one third of patients are women due to skewed X-inactivation.
Autosomal recessive sideroblastic anemia involves mutations in the SLC25A38 gene. The function of this protein is not fully understood, but it is involved in mitochondrial transport of glycine. Glycine is a substrate for ALAS2 and necessary for heme synthesis. The autosomal recessive form is typically severe in presentation.
Genetic syndromes: Rarely, sideroblastic anemia may be part of a congenital syndrome and present with associated findings, such as ataxia, myopathy, and pancreatic insufficiency.
Describe Acquired clonal sideroblastic anemia
Clonal sideroblastic anemias fall under the broader category of myelodysplastic syndromes (MDS). Three forms exist and include refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts and thrombocytosis(RARS-T), and refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS). These anemias are associated with increased risk for leukemic evolution.
Describe Acquired reversible sideroblastic anemia
Causes include excessive alcohol use (the most common cause of sideroblastic anemia), pyridoxine deficiency, lead poisoning, and copper deficiency.
Excess zinc can indirectly cause sideroblastic anemia by decreasing absorption and increasing excretion of copper.
What are some antimicrobials that may lead to sideroblastic anemia?
include isoniazid, chloramphenicol, cycloserine, and linezolid.
What is this and when are they seen?
schistocyte seen in DIC, TTP/HUS, HELLP syndrome or mechanical hemolysis
What are these?
Sickle cells
What are these and when are they seen?
dacrocytes (aka teardrop cells) - a type of poikilocyte that are found in beta thalassemia major, especially after splenectomy. Dacrocytosis can be associated with myelophthisic anemia, commonly caused by myelofibrosis (or any bone marrow infiltration that causes RBCs to be squeezed out and causing this shape)
What are these and when are they seen?
target cells seen in
Liver disease
Alpha-thalassemia and beta-thalassemia
Hemoglobin C Disease
Post-splenectomy: A major function of the spleen is the clearance of opsonized, deformed, and damaged erythrocytes by splenic macrophages. If splenic macrophage function is abnormal or absent because of splenectomy, altered erythrocytes will not be removed from the circulation efficiently. Therefore, increased numbers of target cells may be observed.
Autosplenectomy caused by sickle cell anemia
Why would target cells be seen in liver disease?
Lecithin—cholesterol acyltransferase (LCAT) activity may be decreased in obstructive liver disease. Decreased enzymatic activity increases the cholesterol to phospholipid ratio, producing an absolute increase in surface area of the red blood cell membranes.
What are these and when are they seen?
Heinz bodies in G6PD deficiency
How are Heinz bodies made?
oxidation of Hb-SH groups to -S-S caused Hb precipitation (and subsequent phagocytic damage results in bite cells)
What is this?
A Howell Jolly body seen in pts with functional hyposlenia or asplenia (as tthey are noramlly removed from RBCs by splenic macrophages)
What is a normal MCV?
80-100 fL
What are some causes of microcytic anemia (MCV less than 79 fL)?
- iron deficiency (late)
- Anemia of chronic disease
- thalassemias
- lead poisoning
- sideroblastic anemia
What are some causes of nonhemolytic, normocytic anemias?
ACD and iron deficiency (early)
Aplastic anemia
chronic kidney disease
NOTE: Both ACD and iron deficiency start out as normocytic and progress to microcytic
What are some causes of intrinsic hemolytic, normocytic anemias?
- RBC membrane defects: hereditary spherocytosis
- RBC enyme deficiency: G6PD, pyruvate kinase
- PNH
- Sickle cell anemia
What are some causes of extrinsic hemolytic, normocytic anemias?
- autoimmune
- micro/macroangiopathic
- infections
What are some causes of megaloblastic macrocytic anemias?
folate deficiency
B12 deficiency
orotic aciduria
What are some causes of non-megaloblastic macrocytic anemias?
liver disease
alcoholism
reticulocytosis
What are the lab findings of iron deficiency anemia?
decreased iron, ferritin, and % transferrin saturation (serum iron/TIBC)
increased TIBC
What are the clinical findings of iron deficiency anemia?
fatigue, pink conjunctiva, spoon nails (koilonychia) (below)
What is Plummer-Vinson Syndrome?
triad of iron deficiency anemia, esophageal webbing (below), and atrophic glossitis
A cis deletion in a-thalassemia is more common in _____
Asians
A trans deletion in a-thalassemia is more common in _____
AAs
Describe a 4 allele deletion in a-thalassemia
No a-globin at all; excess y globin forms y4 (Hb Barts)- incompatible with life (causes hydrops fetalis)
Describe a 3 allele deletion in a-thalassemia
HbH disease (excess B-globin forms B4); very little a-globin
Describe B-thalassemias
point mutations in splice sites and promoter sequences decrease B-globin synthesis
prevelant in Mediterranean populations
What are the findings with B-thalassemia minor (heterozygote)?
- B chain is underproduced
- pt is usually asymptomatic
How is B-thalassemia minor diagnosed?
elevated HbA2 (3.5+%) on electrophoresis
What are the findings with B-thalassemia major (homozygote)?
- B-chain is absent causing severe anemia requiring blood transfusion (2ndary hemochromatosis is common here)
- Extramedullary hematopoiessis occurs leading to HSM
- Marrow expansion resulting a characteristic ‘crew-cut’ appearance on skull X-ray, as well as skeletal deformities and chipmunk facies
B-thalassemia carries an increased risk of what?
parvovirus B19-induced aplastic crisis
How does lead poisoning affect the body?
lead inhibits ferrochelatase and ALA dehydratase, decreasing heme synthesis and increasing RBC protoporphyrin
lead also inhibits rRNA degradation, causing RBCs to retain aggregates of rRNA leading to the characteristic ‘basophilic stippling’
How does lead poisoning present clinically?
LEAD:
Lead lines on gingivae (Burton lines) and on metaphyses of long bones on x-ray
Encephalopathy and Erythrocyte basophilic stippling
Abdominal colic and sideroblastic Anemia
Drops- wrist and foot drop
What is the tx of lead poisoning?
Dimerceprol and EDTA
Succimer for chelation in kids
Lead lines on x-ray
What causes hereditary sideroblastic anemia?
x-linked defect in ALA synthase gene
What else can cause sideroblastic anemia?
-myelodysplastic syndrome
alcohol (most common)
-lead
-vit B6 or copper deficiency
isoniazid
How does sideroblastic anemia present in labs?
increased iron and ferritin
low TIBC
What is the tx for sideroblastic anemia?
pyridoxine (B6, cofactor for ALA synthase)
What causes megaloblastic anemia?
impaired DNA synthesis leads to delayed maturation of the nucleus of precursor cells in bone marrow relative to cytoplasm maturation
What are some common causes of folate deficiency?
malnutrition (e.g. alcoholics)
- malabsorption
- increased requirement as in hemolytic anemia and pregnancy
- drugs
What drugs can cause folate deficiency?
methotrexate, trimethoprim, and phenytoin
How does folate deficiency present in labs?
increased homocysteine but normal methylmalonic acid
How does folate deficiency present in clinically?
glossitis but no neurological symptoms
What things cause a B12 insufficiency?
insufficient intake (e.g. veganism)
- malabsorption (e.g. Crohn disease, gastrectomy)
- pernicious anemia
- Diphyllobothrium latum (fish tapeworm)
How does B12 deficiency present in labs?
increased homocysteine AND methylmalonic acid
How does B12 deficiency present clinically?
glossitis AND neurological symptoms including subacute combined degeneration due to B12 involvement in fatty acid pathways and myelin synthesis
What causes orotic aciduria?
inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway) because of a defect in UMP synthase
How does orotic aciduria present?
AR so presents in childhood as failure to thrive, developmental delay, and megaloblastic anemia refractory to folate and B12
How is orotic aciduria tx?
uridine monophosphate
What is the diff between megaloblastic and nonmegaloblastc macrocytic anemia?
megaloblastic has hypersegmented neutrophils
Describe intravascular hemolysis findings
decreased haptoglobin
increased LDH and reticulocytes on blood smear
schistocytes
-hemoglobinuria, hemosiderinuria, and urobilinogen in urine
Describe extravascular hemolysis findings
spherocytes in peripheral smear
increased LDH
no hemoglobinuria/hemosiderinuria
increased unconjugated bilirubin, which can cause jaundice
Describe anemia of chronic disease
inflammation causes increased levels of hepcidin to be released from the liver and bind ferroportin to inhibit iron transport from the intestine and macrophages
What are some conditions commonly associated with anemia of chronic disease?
rheumatoid arthritis, SLE, chronic kidney disease
How does anemia of chronic disease present in labs?
decreased iron and TIBC/transferrin
increased ferritin (primary)
What is aplastic anemia caused by?
failure or destruction of myeloid stem cells due to:
- radiation or drugs (benzene, chloramphenicol, alkylating agents, antimetabolites)
- viral agents
- Fanconi anemia
- idiopathic
What viruses can cause aplastic anemia?
parvovirus B19
EBV
HIV
HCV
Describe the findings of aplastic anemia
pancytopenia with hypocellular bone marrow with fatty infiltrates (below)
Describe hereditary spherocytosis
Defect in proteins interacting with RBC membrane skeletons (spectrin (alpha and beta), ankyrin, band 3 protein, protein 4.2) resulting in small, round RBCs with less surface area and no central pallor (below) that are removed prematurely by the spleen (e.g. extravascular hemolysis)
How does HS present in labs?
MCV normal
increased MCHC and red cell distribution width
positive osmotic fragility test
What is the tx of HS?
splenectomy
What is the most common enzymatic disorder of RBCs?
G6PD deficiency
Describe G6PD deficiency
deficiency of G6PD causes decreased glutathione, increasing the susceptibility of RBCs to oxidative stress. Hemolytic anemia then occurs following some oxidative stress (classically sulfa drugs, fava beans, anatmalarials, and infections)
What are the findings of G6PD deficiency?
back pain, hemoglobinuria a few days after oxidant stress
labs: Heinz bodies and bite cells
“Stress makes me eat bites of fava beans with Heinz ketchup”
Describe pyruvate kinase deficiency
AR disorder caused by defect in PK causing decreased ATP leading to rigid RBCs and subsequent EXTRAvascular anemia in newborns
Describe HbC defect
glutamic acid-to-lysine mutation in B-globin causing an EXTRAvascular hemolytic normocytic anemia
Describe PNH
How does PNH present?
-Coombs hemolytic anemia
pancytopenia
venous thrombosis
How is PNH tx?
eculizumab, a terminal complement inhibitor
What causes sickle cell anemia?
HbS point mutation of valine for glutamic acid in B chain that causes sickling of RBCs in low oxygen states (high altitude, acidosis) leading to anemia and vaso-occlussive disease
When does SCD present?
typically not until after a few months due to low levels of HbS in infants and increased HbF
What are the complications of SCD?
- aplastic crisis (due to parvovirus B19)
- autosplenectomy
- painful crises including dactylitis, acute chest syndrome, stroke, and avascular necrosis
- renal papillary necrosis
SCD predisposes to ________ osteomyelitis
Salmonella
How is SCD tx?
hydration, hydroxyurea
Autoimmune hemolytic anemias are usually ______ positive
Coombs
Describe Warm agglutinin AHA
IgG mediated chronic anemia seen in SLE and CLL and with certain drugs (e.g. a-methyldopa)
Describe Cold agglutinin AHA
IgM mediated hemolytic anemia triggered by cold, commonly seen in CLL, mycoplasma pneumonia infections, and infectious mono
Describe a direct Coomb’s test
anti-Ig Ab (aka Coomb’s reagent) is added to pts blood and RBCs agglutinate if they are coated with Ig
Describe an indirect Coomb’s test
Normal RBCs are added to a pt’s serum and if the serum has anti-RBC surface Ig, RBCs agglutinate when Coomb’s reagant is added
What happens in microangiopathic anemia?
RBCs are damaged when passing through obstructed or narrowed vessel lumina (seen in DIC, TTP/HUS, SLE and malignant HTN) causing schistocytes
How does hemochromatosis present in labs?
decreased transferrin/TIBC
increased serum iron, ferritin, and % transferrin saturation (serum iron/TIBC)
transferrin transports iron in blood
TIBC is an indirect measure of transferrin
ferritin stores iron
What is neutropenia defined as?
less than 1500cells/mm3 as seen in sepsis/infection, SLE, radiation, etc.
What is lymphopenia defined as?
less than 1500cell/mm3 as seen in HIV, DiGeorge Syndrome, SCID, SLE, corticosteroids, etc.
Why do corticosteroids cause neutrophilia but lympho- and eosinopenia?
Steroids decrease activation of neutrophil adhesion molecules, impairing migration out of vasculature, while they sequester eos in lymph nodes and cause apoptosis of lymphocytes
Lead poisoning affects what enzymes?
ferrochelatase and ALA dehydratase
What serum markers are elevated in lead poisoning?
protoporphyrin and delta-ALA
What enzyme is affected by acute intermittent porphyria?
porphobiliogen deaminase
What serum markers are elevated in acute intermittent porphyria?
porphobilogen
delta-ALA
coporphobilinogen (in urine)
What are the symptoms of acute intermittent porphyria?
5P’s:
Painful abdomen
Port wine-colored urine
Polyneuropathy
Psychological disturbances
Precipitated by drugs (e.g. CYP450 inducers, alcohol)
What is the tx of acute intermittent porphyria?
glucose and heme
What enzyme is affected in porphyria cutanea tarda?
uroporphyrinogen decarboxylase, causing a blistering cutaneous photosensitivity (vampires!!)
