Disorders of Red Blood Cells Flashcards
How do you differentiate iron deficiency microcytic anemia from thalassemia microcytic anemia?
Look at the Rbc Distribution Width (RDW)
- Iron deficiency will have a High RDW
- Thalassemia will have a low RDW
In the presence of an anemia what can the reticulocyte count indicate?
In the presence of anemia a…
High count = over production or loss of storage of RBCs
Low Count = Impaired production (bone marrow destruction)
What are Howell Jolly bodies and what is it associated with?
- Nuclear remnants
- Indicative of asplenia or severe anemia
What are targets in RBCs and what is it associated with?
1) Concentrations of hemoglobin
2) Assoc. with Hemoglobin C disease, Asplenia, Liver disease, Thalassemia
think: HALT said the hunter to his target
What are Heinz bodies and what are they associated with?
- Large, blue intracytoplasmic inclusions attached to inner cell membrane that consists of precipitated hemoglobin
- Assoc. with G6PD, thalassemia, and Oxidant drugs (Primaquine and Dapsone)
What enzyme is inhibited by lead poisoning?
Ferrochelatase, ALA dehydratase, and pyrmidine 5-nucleotidase
When looking at a Red Cell Histogram what does a left shift indicate? Right?
Left = microcytic red cells Right= macrocytic red cell
How are reticulocytes identified?
Polychromasia. Granular netowrk of polyribosomes/rough ER that clump and are observed with staining.
Name the different cell types in erythropoiesis.
1) Proerythroblast
2) Basophilic erythroblast
3) Polychromatophilic erythroblast
4) Orthochromatophilic erythroblast
5) Reticulocyte
6) Erythrocyte
What is the difference between an orthophilic erythroblast and a reticulocyte?
Reticulocyte does not have a nucleus and has polychromasia
How long does it take for the body to respond to decreased rbcs due to anemia/blood loss?
7 days. It takes 5 days for maturation from stem cell to reticulocyte
What are the effects of massive bone marrow proliferation due to untreated anemia?
1) Expansion of the medulla
2) Thinning of the cortical bone
3) Resporption of cancellous bone
4) Secondary Bone Formation (prominent cheekbones and skull changes)
What is an infectious cause for pure red cell aplasia?
Parvovirus
What is the cause of basophilic stippling?
1) Thalassemia
2) Anemia of chronic disease
3) Lead poisoning
How can you differentiate sideroblastic anemia from other forms of microcytic hypochromic anemias?
Sideroblastic anemia has a high serum iron level due to the fact that this disease is caused by heme synthesis problems
What metabolites are high in a pt. with lead poisoning?
1) ALA increased in urine
2) Protoporphyrin IX in blood
Causes of macrocytosis anemia?
1) Rapid RBC turnover (increased reticulocytes)
2) Chronic alcoholism
3) Megaloblastic anemia
4) Orotic aciduria
What lab value do you use to confirm B12 deficiency?
Serum Homocysteine or methylmalonic acid (should be elevated)
What does hemoglobin in the urine, decreased haptoglobin, and increased bilirubin indicate?
Intravascular hemolysis
What is a positive Coomb’s test indicative of?
Autoimmune hemolytic anemia
How can you differentiate extravascular from intravascular hemolysis?
1) Intravascular will have hemoglobinemia, hemoglobinuria, and hemosiderinuria.
2) Jaundice is found in both
3) Increased erythropoietin
Autosomal dominant disease of rbc that is due to an insufficiency of membrane skeletal proteins which results in a lack of deformability resulting in hemolysis
Hereditary Spherocytosis
What proteins are affected in hereditary spherocytosis?
1) Spectrin
2) Ankyrin
3) Band 3
What is the primary cause of hemolysis in hereditary spherocytosis?
The spleen. Cell are not able to pass through the cords of Billroth
What is the most likely cause of aplastic crises in a pt. with Hereditary Spherocytosis?
Parvovirus infection. This occurs because virus targets erthroprogenitor cells. Leads to decreased erythropoeisis which is constantly required for HS
What reaction is glucose 6 phosphate dehydrogenase involved with?
Reaction: Glucose 6 phosphate –> 6-phosphogluconate
Reduces NADP –> NADPH
What X linked disease results in episodic hemolysis due to a misfolding of an important protein involved with glutathione pathway which releives oxidative stress?
Glucose 6 phosphate dehydrogenase deficiency
What is the cause of episodic hemolysis in G6PD deficiency? What initiates this?
Oxidative stress
1) Infections
2) Typhoid fever
3) Oxidant drugs (sulfonamides, anti-malarials)
4) Fava beans
How do Heinz bodies form in G6PD deficiency?
The increased in oxidative stress results in the crosslinking of sulfhydrl groups which precipitate at the membrane resulting in dark inclusions known as Heinz bodies
Why is episodic hemolysis observed in G6PD deficiency?
1) Because hemolysis only occurs in older rbcs
Older cells = decreased enzymes (do not produce)
Younger cells= normal amount of enzymes
What autosomal recessive disease results in chronic hemolysis due to a defect in a protein involved with the conversion of phosphoenol pyruvate to pyruvate?
Pyruvate Kinase Deficiency
Why does Pyruvate kinase deficiency cause hemolysis?
The absence of the conversion of phosphoenol pyruvate to pyruvate results in a decrease in ATP.
Decreased ATP leads to loss of membrane integrity
What are Schistocytes and what are they associated with?
1) Fragmented RBCs due to mechanical trauma
2) Associated with Stenotic valve, DIC, TTP/HUS
Why do children have skull deformities with chronic untreated anemia and adults do not?
Children already have hematopoeisis going on throughout body so it must expand in the skull. Adults just turn on hematopoeisis within the long bones
What are causes of hypochromic microcytic polychrmoasia anemia?
1) Beta Thalassemia
2) Treated iron deficiency
What is the mutation that causes sickle cell anema (HbS)?
1) Point mutation of the 6th codon in the beta globin 2) Results in replacement of glutamate with valine
What is the mutation found in HbC?
1) Point mutation of the 6th codon in the beta globin
2) Results in replacement of glutamate with lysine
3) Increases sickling in sickle cell trait
How does the Sickle shape form in Sickle cell anemia?
When HbS becomes deoxygenated it results in polymerization and aggregation that causes the cytoplasm to become viscous. Together these cause a sickle shape
What four factors influence sickling of rbcs?
1) Interaction with other hemoglobin
2) Intracellular pH
3) Mean cell hemoglobin concentration
4) Transit time through microvascular beds
What determines the severity of chronic hemolysis in Sickle cell anemia?
1) The percentage of irreversibly sickled cells
What is the difference in where spherocytes and sickle cells are captured in the spleen?
1) Spherocytes = cords of Billroth
2) Sickle cells = cords and sinusoids
How does autosplenectomy, a common occurnence in Sickle cell patients, occur?
1) It occurs by chronic erythrostasis that leads to splenic infarction, fibrosis, and progressive shrinkage
Clinical features of Sickle cell disease
1) Severe hemolytic anemia
2) Vaso-occlusive (pain) crises - common in bone, brain, liver, lungs, spleen
3) Sequestration crises (in children with intact spleens)- causes massive splenomegally
4) Aplastic crises - occurs with Parvovirus infx
5) Chronic hypoxia- results in impaired growth and development
6) Hyposthenuria (unable to concentrate urine)
7) Increased susceptibility to encapsulated organisms
8) Gall stones
What is used to treat Sickle cell anemia and why?
1) Hydroxyurea
2) Inhibits DNA synthesis resulting in an increase in HbF and an anti-inflammatory effect due to a decrease in wbc production
What is the cause of ineffective erythropoeisis in beta thalaseemia?
1) The accumulation of alpha globins results in membrane damage causing ineffective erythropoeisis
What are the complications of ineffective hematopoiesis for those with severe beta thalassemia?
1) It causes extramedullary hematopoiesis
2) Also leads to increase in absorption of dietary iron leading to iron overload
3) Iron overload complicates blood transfusions
What are the two clinical syndromes of beta thalassemia?
1) Beta thalassemia major - requires blood transfusions, generally homozygous, results in severe ineffective hematopoeisis; HbF major
2) Beta thalassemia minor - usually asymptomatic or mild anemia; generally heterozygous; HbA2 major
What are the four clinical syndromes of alpha thalassemia?
1) Silent Carrier State (1 deletion)
2) Alpha Thalassemia trait (2 deletions)
3) Hemoglobbin H Disease (3 deletions)
4) Hydrops fetalis (4 deletions)
What type of tetramers form in Hemoglobin H disease?
HbH - tetramer of beta globin; high affinity for oxygen; forms with deletion of 3 alpha genes
What type of tetramers form in Hydrops fetalis?
Bart’s hemoglobin- tetramer of gamma globin; deletion of all four alpha genes
What is Hemoglobin SC disease?
It is a combination of HbS and HbC that increases sickling
What disease is due to an X linked, acquired, mutation that results in increased complement mediated RBC lysis?
Paroxysmal Nocturnal Hemoglobinuria (PNH)
What does phosphatidylinositol glycan complementation group A (PIGA) gene found defective in paroxysmal nocturnal hemoglobinuria encode?
PIGA encodes cell surface proteins for rbcs
1) CD55
2) CD59 (inhibitor of C3 convertase)
3) C8 binding protien
What diseases cause spherocytes?
1) Hereditary spherocytosis
2) Immunohemolytic anemia
3) Pyruvate kinase deficiency
4) Anything that causes partial damage to membrane
What are the causes of secondary Warm Antibody type of Autoimmune hemolytic anemia?
1) Predispositions (SLE or lymphoid neoplasm)
2) Drug exposure (Antigenic drugs-binds to surface proteins and is identified by Ig or Tolerance breaking drugs- cause creation of Ig against RBC antigen)
What are the different types of Autoimmune Hemolytic Anemia?
1) Warm Antibody Type (IgG)- assoc. drugs/predisposition; extravascular hemolysis
think: Warm is GGGGreat!
2) Cold Agglutinin Type (IgM)- assoc. infx (CMV, EBV, Mycoplasma, HIV); Reynauds phenomenon, intravasucar hemolysis
think: Cold ice cream yuMMM!
What are the microangiopathic disorders that can cause hemolytic anemia?
1) Disseminated Intravascular Coagulation (DIC)
2) Thrombotic thrombocytopenic purpura (TTP)
3) Hemolytic Uremic Syndrome (HUS)
4) Maligant Hypertension
What causes hemolytic uremic syndrome? What is characteristic histology finding?
1) Infection of Enterhemorrhagic E. coli that results in endothelial injury
2) Schistocytes
What causes Thrombotic Thrombocytopenic purppura (TTP)?
A dysregulation of vWF (involved with clotting) due to a deficiency in ADAMTS13
What two interactions are B12 involved in? What metabolites accumulate in B12 deficiency?
1) Homocysteine –> Methionine (results in THF)
2) Methylmalonyl CoA –> Succinyl CoA
3) Homocysteine and Methylmalonyl
How do neurological complications of B12 deficiency occur?
1) Neurological complications are due to an accumulation of abnormal fatty acids
2) Fatty acids accumulate due to the accumulation of methylmalonyl acid that builds up
What are the three antibodies observed in Pernicious Anemia?
1) Type I (blocks binding of B12 to intrinsic factor)
2) Type II (blocks binding of intrinsic factor/B12 complex to the ileal receptor)
3) Type III (targets the parietal cells by recognizing the subunits of the gastric protein pumps)
What drives Pernicious anemia?
1) Autoimmune attack that is T cell driven on the gastric mucosa
What are the clinical findings of a pt. with Pernicious Anemia?
1) Gastric atrophy along with intestinalization (metaplasia parietal to goblet)
2) Glazed and beefy tongue
3) Megaloblastic rbcs
4) Demylation of the lateral and dorsal tracts of the spinal cord (causes sensory ataxia and spastic paraparesis)
How do you differentiate megaloblastic anemia caused by folate deficiency or B12 deficiency?
1) Folate = low folate, High homocysteine, normal methylmalonic acid, no neurological problems
2) B12 = low B12, high homocysteine, high methylmalonic acid, neurological problems (ascending and descending demyelination)
What are causes of folate deficiency?
1) Inadequate intake
2) Increased requirement (pregnancy, cancer, hemolytic anemia)
3) Impaired utilization (inhibition of enzymes)
What are causes of B12 deficiency?
1) Pernicious anemia
2) Ileum resection
3) Absence of pancreatic enzymes
4) Achlorydia
5) Crohn’s disease
6) Diphyllobothrium latum (tape worm)
What is iron deficiency in adult men and postmenopausal women until proven otherwise?
Chronic blood loss in the gastrointestinal tract
What are the causes of iron deficiency?
1) Inadequate amount in diet
2) Impaired absorption
3) Increased requirement (pregnancy)
4) Chronic blood loss
What does the bone marrow look like in a pt. with iron deficiency?
When using a prussian stain there is NO evidence of iron present within the macrophages
What is Plummer- Vinson syndrome
1) Iron deficiency
2) Esophageal webs
3) Glossitis
What are specific causes of aplastic anemia?
1) Idiopathic
2) Chemical agents (alkylating, antimetabolite, benzene, chloramphenicol)
3) Whole body irradiation
4) Viral infection (CMV, HIV, EBV, Herpes Zoster)
5) Inherited (Fanconi anemia and telomerase defects)
What is the difference between relative and absolute polycythemia?
1) Relative - decreased plasma volume, increased hemoconcentration
2) Absolute - increase of red cell mass
What is the cause of a myelophthisic anemia?
Bone occupying lesions due to metastatic cancer, granulomatous disease, or myeloproliferative disease.
What are causes of relative polycythemia?
1) Dehydration
2) Gaisbock (stress) syndrome - obese, anxious, hypertensive
What are causes of absolute polycythemia?
1) Primary - intrinsic defect in the hematopoietic precursors
2) Secondary - response to increased levels of erythropoeitin
Causes of absolute secondary polycythemia?
1) Compensatory response to lung dx., high altitude
2) Paraneoplastic
3) Hemoglobinopathies
4) Inherited defects that stabilize HIF-1alplha
What cytokine is associated with anemia of chronic disease? What does it result in?
1) IL-6
2) Increased Hepcidin –> decreased Ferroportin
3) Decreased Ferroportin results in Iron remaining in macrophages and intestinal wall cells
4) Low erythropoeitin due to high Hepcidin
What are the causes of anemia of chronic disease?
1) Chronic infection (osteomyelitis, neoplasm, chronic immune disorder)
2) Neoplasm
3) Chronic immune disorder
What is hypersplenism and why does it occur?
1) Syndrome that produces anemia, thrombocytopenia, and leukopenia alone or in combination
2) Splenomegaly causing prolonged exposure of components to macrophages in the spleen
What are causes of congestive splenomegally? (3 total)
1) Intrahepatic disorders (cirrhosis, shistosomiasis)
2) Systemic venous congestion (right heart failure)
3) Obstruction of the extrahepatic/splenic veins (tumors)
What are factors that predispose spleens to rupture?
1) Malaria
2) Infectious mononucleosis
3) Typhoid fever
4) Lymphoid neoplasms
What causes dacryocytes?
1) Dacryocytes = tear drop shaped cells
2) Primary myelofibrosis
What are the general causes of microcytic anemia? What are the 4 causes?
1) Decreased iron and decreased globin
2) Iron deficiency, sideroblastic anemia, thalassemia, and anemia of chronic disease
What are the phases of iron deficiency?
1) Decreased storage (low Ferritin/High Total Iron Binding capacity = increased transferrin)
2) Decreased serum (low serum iron and low transferrin saturation)
3) normocytic anemia
4) microcytic, hypochromic anemia
Bite cells
G6PD deficiency (x linked)
Ringed sideroblasts
1) Siderolbastic anemia
2) Excess iron in mitochondria
Absent beta chain
Beta thalasemia major
What is commonly observed as a complication to beta thalassemia major?
1) Secondary hemochromatosis due to chronic requirement of blood transfusions
Pt. presents with lines on gingivae and on long bones via xray; encephalopathy; erythrocyte basophilic stippling; abdominal colic, Wrist and foot drop
Lead poisoning
Tx for lead poisoning
Dimercapol and EDTA
Defect in heme sythesis due to defect in ALA synthase or reversible causes such as alcohol, lead and isoniazid
Sideroblastic anemia
What causes reversible sideroblastic anema?
1) Lead
2) Alcohol
3) INH (causing B6 deficiency)
What are iron study findings for sideroblastic anemia?
1) Increased Iron
2) Normal TIBC
3) Increased ferritin
Defect in UMP synthase that results in megaloblastic anema as well as increased orotic acid
Orotic aciduria
How do you differentiate OTC deficiency from orotic aciduria?
OTC has hyperammonemia; orotic aciduria does not
What would iron studies for a pt. with anemia of chronic disease come back as?
1) Decreased Iron, Decreased TIBC, Increased Ferritin
Normocytic hemolytic intrinsic causes
1) Hereditary spherocytosis (extravascular hemolysis)
2) G6PD deficiency (extravascular hemolysis)
3) Pyruvate kinase (Extravascular hemolysis)
4) Paroxysmal nocturnal hemoglobinuria
5) HbC disease
6) Sickle cell diseae
Glutamate –> valine in position 6 of Beta globulin gene
Sickle cell
Glutamate –> Lysine in position 6 of beta globulin gene
HbC
Normocytic hemolytic extrinsic causes
1) Autoimmune
2) Microangiopathic (TPP, DIC, HUS, SLE, malignant HTN)
3) Macroangiopathic (valve or aortic stenosis)
What is a direct coombs test? indirect?
1) Direct = anti-Ig antibody added to pt. blood; RBCs agglutinate if covered with Ig
2) Indirect = normal RBCs are added to pt. blood;
What is the cause of acute intermittent porphyria and what substrate builds up?
1) Defective porphobilinogen deaminase
2) Porphobilinogen
Pt. presents with painful abdomen, red urine, polyneuropathy, psychological disturbances and may have been precipitated by drugs
Acute intermittent porphyria
Defect in porphobilinogen deaminase
acute intermittent porphyria
What is the cause of porphyria cutanea tarda and what substrate builds up?
1) Uroporphyrinogen decarboxylase
2) Urophorphyrin
Pt. presents with blistering cutaneous photosensitivity, tea colored urine. Most common porphyria
Porphyria cutanea tarda
Defect in uroporphryinogen decarboxylase
Porphyria cutanea tarda
What is the inheritance pattern of sickle cell anema
autosomal recessive
What is the serum protein that binds to free hemoglobin and promotes its uptake in the reticuloendothelial system found in an intravascular hemolysis?
Haptoglobin
What is the result of a transfer of glutamate to valine in the 6th position of chromosome 11? What does this amino acid substitution result in?
1) Sickle cell anemia
2) Results in a not charged valine increasing the aggregation of heme in an deoxygenated state due to the beta chain fitting into an alpha chain of another hemoglobin
What is the reticulocyte index in a pt. whose bone marrow is responding to excessive RBC destruction
2%
What is the cause of intravascular hemolysis due to a transfusion? extravascular?
1) ABO (very severe)
2) Minor antigen ( less severe and has a delayed response)
What must you check in order to determine a hemolytic anemia?
1) Haptoglobin
2) LDH
3) Bilirubin levels
What are the causes of normocytic anemia?
1) Renal disease (decreased erythropoetin)
2) Aplastic anemia
3) Bone marrow fibrosis
4) Tumor
5) Anemia of chronic disease
Elderly with anemia: you should think…
Colon cancer
What should be given with an oral dose of iron?
Vitamin C (orange juice, ect)
What does the RDW measure?
1) Measures the variation in RBC size
What you observe in electrophoresis of a thalassemia?
General decrease in all proteins (due to alpha globin’s importance in all forms of heme)
What is the genotype of Cooley’s anemia?
1) Homozygous mutation of beta globin gene on chromosome 11
What pop. is assoc. with Cooley’s anemia?
Mediterranean
What does skull Xray with “Crew cut” appearance indicate with a microcytic anemia?
Cooley’s anemia
How is thalssemia treated and what are the complications of this treatment?
1) Blood transfusions to replete hemoglobin
2) Secondary hemochromotosis leading to CHF
What drug is used along with transfusions for thalassemia pt.?
Desferrioxamine (chelating agent that eliminates excess iron)
What symptoms should you look for in a pt. with aplastic anemia?
1) Fatigue, pallor
2) Easy bruising and petechiae
What are the extrinsic causes of hemolyitc anemia?
1) Mechanical stress
2) Drugs
3) Autoimmune
What are the intrinsic causes of hemolytic anemia?
Think: what does an rbc consist of… membrane, hemoglobin, and enzymes
1) Sickle cell
2) Hb H disease
3) Hereditary Spherocytosis
4) Paroxysmal nocturnal hemoglobinuria
5) G6PD deficiency
6) Pyruvate kinase deficiency
What is required for diagnosis of sickle cell disease, beside presence of anemia and peripheral smear?
1) Need hemoglobin electrophoresis
How do you treat a pt. with sickle cell anema?
1) Advise staying away from elevation, dehydration, and treating infections quickly
What is the best treatment for hereditary spherocytosis?
1) Splenectomy
2) Prophylactic treatments to prevent infection by encapsulated organisms
What drugs induce hemolysis in pt. with G6PD deficiency
think: hemolysis IS PAIN
1) INH
2) Sulfa drugs
3) Primaquine
4) Aspirin
5) Ibuprofen
6) Nitrofuratoin
What is used to treat paroxysmal nocturnal hemoglobinuria?
1) Glucocorticosteroids
2) Bone marrow transplant
