RBC Pathology 1 Flashcards

1
Q

What is the basic definition of anemia?

A

A reduction of the total RBC mass below normal limits. It diagnosed using Hct. and Hb concentration.

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2
Q

What is the definition of the following?

Mean cell volume

Mean cell hemoglobin

Mean cell hemoglobin concentration

Red cell distribution width

A

Mean cell volume: the average volume of a red cell in fL.

Mean cell hemoglobin: the average content (mass) of hemoglobin per red cell in pG.

Mean cell hemoglobin concentration: the average concentration of hemoglobin in a given volume of packed red cells in g/dL.

Red cell distribution width: the coefficient of variation of red cell volume.

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3
Q

What is the clinical presentation of a patient with anemia?

A

They may appear pale, weak, malaised and easily fatigued with DOE.

The chronic hypoxia may result in fatty change in the liver, myocardium and kidneys.

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4
Q

The effects of acute blood loss are mainly due to what?

If the bleed is large enough to decreased BP, what compensatory changes occur?

What is the major concern during recovery of the bleed?

A

The loss of intravascular volume, which if massive, can lead to cardiovascular collapse, shock and death.

If the bleed is significant enough to lower BP, there will be mobilization of granulocytes (leukocytosis) and elevated reticulocyte ct.

During early recovery, thrombocytosis occurs and may lead to clots.

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5
Q

How long does it take for reticulocytes to be produced after an acute bleed?

A

5-7 days

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6
Q

What 3 features are noticed in hemolytic anemias?

A

Shortened RBC lifespan below the typical 120 days.

Elevated EPO levels and a compensatory increase in erythropoiesis.

Accumulation of RBC products due to hemolysis.

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7
Q

Chronic anemia is induced only when:

A

The rate of loss exceeds the regenerative capacity of the marrow (1) or when iron reserves are depleted (2) and iron-deficiency anemia appears.

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8
Q

What is the major cause of extravascular hemolytic anemia?

What are the typical signs/symptoms? (3)

A

Lack of deformability of red cells in the sinusoids.

Anemia, splenomegaly and jaundice.

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9
Q

What can cause intravascular hemolytic anemia?

What are the typical signs/symptoms? How can it be differentiated from the extravascular type?

A

Mechanical injury, complement activation, intracellular parasites or toxins.

Anemia, hemoglobinemia, hemoglobinuria and jaundice. Splenomegaly is typically NOT a feature (it is in extravascular anemia)!

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10
Q

What is the role of haptoglobin (“suicide molecule”)?

A

It binds free Hb to prevent its excretion in urine. It is used to measure the amount of free Hb. It is decreased in hemolytic anemias.

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11
Q

What kind of BR is elevated in uncomplicated hemolytic anemias?

A

Unconjugated BR

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12
Q

What do the red cells look like in hereditary spherocytosis (HS)?

A

The RBC cell membrane skeleton is affected and renders the red cells spherical, less deformable and vulnerable to splenic sequestration and destruction.

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13
Q

What is the inheritance pattern of hereditary spherocytosis?

RBCs in HS are abnormally sensitive to what?

What lab finding is elevated in HS?

A

AD (75%)

Osmotic lysis when incubated in hypotonic solutions.

Mean cell Hb concentration (MCHC) is elevated.

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14
Q

What are the symptoms of HS?

What is the clinical progression of HS?

What can be done to treat the anemia and its complications?

A

Anemia, splenomegaly and jaundice. In about 25% of patients the disease is asymptomatic; in the remaining 75%, compensatory changes are outpaced producing a chronic hemolytic anemia of mild to moderate severity. Gallstones may occur also.

It is generally stable, but sometimes punctuated by aplastic crises, often triggered by an acute parvovirus infection, due to increased splenic destruction.

Splenectomy treats the anemia and its complications, but increases the risk of sepsis (spleen filters blood-borne bacteria).

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15
Q

What is the biochemical consequence of glucose-6-phosphate dehydrogenase deficiency?

What is the inheritance?

What is the characteristic of G6PD deficiency?

A

G6PD reduces NADP to NADPH, which goes on to create reduced glutathione which helps in protecting against oxidant injuries.

X-linked recessive.

Episodic hemolysis caused by exposures that generate oxidant stress, most often due to infection (hepatitis, pneumonia and typhoid fever). Certain drugs and foods ma also induce this stress.

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16
Q

What do the RBCs in G6PD look like on a smear?

What symptoms ensue after exposure to an oxidant?

Which patients may have a greater degree of hemolysis?

A

They appear as “bite cells” because splenic macrophages pluck out Heinz bodies (precipitates of denatured globin).

Acute intravascular hemolysis, marked by anemia, hemoglobinemia and hemoglobinuria 2-3 days post exposure to oxidants.

The hemolysis is greater in individuals withe highly unstable G6PD Mediterranean variant.

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17
Q

Which globin chains are produced before birth and into the post-natal period?

Which globin chains are produced in smaller quantities before birth, but begin to increase shortly before birth?

Which globin chains are produced before birth, but taper off around week 24?

Which globulin chains are produced beginning at birth only, and are produced in a small quantity?

A

Alpha

Beta

Gamma

Delta

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18
Q

What are the following lab values in males vs. females?

Hb (g/dl)

Hct.

RBC ct. (x 1 million)

A

Hb (g/dl): 13.6-17.2 (M), 12.0-15.0 (F).

Hct.: 39-49% (M), 33-43% (F).

RBC ct. (x 1 million): 4.3-5.9 (M), 3.5-5.0 (F)

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19
Q

What is the inheritance of sickle cell disease (SSD)?

What is the mutation?

What occurs to the RBC as a result?

A

AR

A point mutation in the beta-globin that leads to polymerization of deoxygenated Hb (Glu is replaced with Val).

There is RBC distortion, hemolytic anemia, microvascular obstruction and ischemic tissue damage.

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20
Q

What is seen on microscopy in patients with SSD? (3)

A

Sickled cells
Anisocytosis (unequal size)
Poikilocytosis (abnormal shape).

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21
Q

What lab changes are seen in SSD? (4)

What signs/symptoms may exist in SSD? (5)

What tends to be the most common symptoms in kids?

A

Severe hemolytic anemia (18-30%), reticulocytosis and elevated BR, depleted NO by haptoglobin.

Vaso-occlusive crises causing severe pain (bone, lungs, liver, brain, spleen and penis).
Acute chest syndrome (vaso-occlusive crisis in the lungs) - cough, fever, CP and infiltrates.
Priapism - hypoxic damage and ED.
Stroke
Retinopathy

Severe bone pain that is hard to differentiate from osteomyelitis.

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22
Q

In kids with SSD and a spleen, what “crisis” may occur?

An aplastic crisis in SSD stems from what?

What 2 processes may cause death acutely in SSD?

What is responsible for generalized impairment of growth and development in SSD?

Aside from what is listed, what else is a major threat in SSD?

A

Sequestration crisis - a massive entrapment of sickled RBCs leads to rapid splenic enlargement, hypovolemia and possible shock.

Infection of RBC progenitors by parvovirus B19.

Sequestration crisis and acute chest syndrome.

Chronic hypoxia.

Infection by encapsulated organisms, commonly S. pneumoniae and H. flu.

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23
Q

What is used to diagnose HbS and rule-out other hemoglobinopathies?

How is SSD diagnosed prenatally?

A

Hemoglobin electrophoresis.

Analysis of fetal DNA by amniocentesis or chorionic biopsy.

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24
Q

What are symptoms of hemoglobin C disease?
What are the symptoms of hemoglobin SC disease?

What alleles are affected in hemoglobin C disease?
How does this differ from hemoglobin SC disease?

A

Hb C disease: typically asymptomatic. It may exhibit mild (chronic) hemolytic anemia and the sequelae associated with it.
Hb SC disease: it is a symptomatic sickling disorder.

Hb C disease: both beta chains are affected (2-3% in AAs).
Hb SC disease: only one beta chain is affected (8% of AAs), thus it much more common.

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25
Q

What chromosome codes the 2 alpha-chains? How many genes?

What chromosome codes the 2 beta-chains? How many genes?

A

Chr. 16 - 2 alpha-globin genes.

Chr. 11 - 1 beta-globin gene.

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26
Q

What causes the hematologic consequences in thalassemias?

A

Both the deficiency of the globin chain involved and the excess of the other chain (i.e. a-thalassemia leads to decreased [alpha-chain] and elevated [beta-chain]).

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27
Q

How do thalassemias cause anemia? How is this different than other inherited forms?

A

Through decreased RBC and decreased RBC lifespan. Hemolysis is the primary route of anemia in other inherited disorders.

28
Q

What are the genotypes of the following B-thalassemias?

B-thalassemia major

B-thalassemia intermedia

B-thalassemia minor

A

B-thalassemia major: homozygous

B-thalassemia intermedia: variable

B-thalassemia minor: heterozygous

29
Q

What is the severity of the following?

B-thalassemia major

B-thalassemia intermedia

B-thalassemia minor

A

B-thalassemia major: severe; requires blood transfusions.

B-thalassemia intermedia: severe; does NOT require transfusions.

B-thalassemia minor: asymptomatic with mid or absent anemia; cell abnormalities seen.

30
Q

What is the molecular pathology of B-thalassemia?

A

Mainly point mutations leading to defects in the transcription, splicing or translation of B-globin mRNA.

31
Q

What is the severity of the following a-thalassemias?

Silent carrier (-/a, a/a)

a-thalassemia trait (Asian: -/-, a/a; African: -/a, -/a)

HBH disease (-/-, -/a)

Hydrops fetalis (-/-, -/-)

A

Silent carrier (-/a, a/a): asymptomatic without RBC abnormality

a-thalassemia trait (Asian: -/-, a/a; African: -/a, -/a): asymptomatic with mild/absent anemia (like B-thalassemia minor).

HBH disease (-/-, -/a): severe, resembles B-thalassemia intermedia.

Hydrops fetalis (-/-, -/-): lethal in utero without transfusions.

32
Q

By what 2 mechanisms does impaired B-globin synthesis result in anemia?

A

The deficit in HbA synthesis produces “underhemoglobinized” hypochromic, microcytic red cells with poor oxygen transport capacity.

Diminished survival of RBCs and their precursors, which results from imbalance in alpha and beta-globin synthesis.

33
Q

In severe B-thalassemia, 70-85% of RBC precursors suffer what fate?

What occurs as a result?

A

The precursors succumb to membrane damage and undergo apoptosis.

It leads to ineffective erythropoiesis. The RBCs released from the marrow also contain inclusions (unpaired alpha chains) and have membrane damage, leaving them prone to splenic sequestration and extravascular hemolysis.

34
Q

When does B-thalassemia major present?

What is the clinical course?

What Hb type is markedly elevated?

A

6-9 mo. after birth once Hb synthesis switches from HbF to HbA.

The clinical course is brief unless transfusions are given. Untreated children have GR and die early from anemia. Cheekbones and other bony prominences may be seen. HSM is als seen due to EMH.

35
Q

What complication may occur in B-thalassemia major patients receiving transfusions?

A

Cardiac disease resulting from progressive iron overload and secondary hemochromatosis. It is an important cause of death in heavily transfused patients/

36
Q

What treatments exist for B-thalassemia major?

A

With transfusions and iron chelation, survival into the 3rd decade is possible.

Hematopoietic stem cell transplant is the only therapy offering a cure and is being used more often.

37
Q

How do RBCs appear in B-thalassemia minor on a smear?

What Hb type is usually elevated?

Why is recognition of B-thalassemia minor important? (2)

A

Hypochromia, microcytosis, basophilic stipping and target cells. Mild erythroid hyperplasia is seen on BM.

Increased HbA2 - useful in diagnosis.

(1) it superficially resembles the hypochromic microcytic anemia of iron deficiency.
(2) it has implications for genetic counseling.

38
Q

What are hemoglobin Barts and HbH?

A

Hb Barts: excess unpaired y-globin chains from y4 tetramers in newborns with a-thalassemia.

HbH: excess B-globin chains form B4 tetramers in older kids and adults with a-thalassemia.

39
Q

What is the common molecular cause of alpha-thalassemias?

A

Gene deletions

40
Q

What acquired mutation is seen in paroxysmal nocturnal hemoglobinuria (PNH)?

What makes it unique?

A

Mutations in phosphatidylinositol glycan complementation group A gene (PIGA).

It is very rare, but is the only hemolytic anemia caused by an acquired genetic defect.

41
Q

What is meant by B0 and B+?

A

B0 = absent B-globin synthesis

B+ = reduced, but detectable B-globin synthesis.

42
Q

What kind of hemolysis occurs in PNH? How?

What is the major cause of death in patients with PNH? What is another unique consequence?

How is it diagnosed?

A

Intravascular hemolysis caused by C5b-C9 MAC.

Thrombosis. 40% of patients have venous thromboses involving the hepatic, portal or cerebral vv.
5-10% of patients eventually develop AML or MDS.

Flow cytometry.

43
Q

Why is it believed that hemolysis in PNH occurs at nighttime?

What kind of anemia occurs in PNH?

A

There is a mild decreased in pH while sleeping, which increases the activity of complement.

It is usually mild to moderate in severity. The loss of heme-iron in urine eventually leads to iron-deficiency anemia which can exacerbate the fundamental anemia disorder.

44
Q

Warm antibody type anemia

What antibody is involved?
What are the causes?

A

IgG antibodies active at 37 degrees.

Primary - idiopathic.
Secondary - SLE, drugs and lymphoid neoplasms.

45
Q

Cold agglutinin type anemia

What antibody is involved?
What are the causes?

A

IgM antibodies active at 37 degrees.

Acute - mycoplasma, mono.
Chronic - idiopathic, lymphoid neoplasms.

46
Q

Cold hemolysin type anemia

What antibody is involved?
What are the causes?

A

IgG antibodies active below 37 degrees.

Rare - occurs in children after a viral infection.

47
Q

How is an autoimmune anemia detected?

A

Direct Coombs test: pt.’s RBCs are mixed with serum antibodies specific for human Ig or complement. If either Ig or complement is present on the surface of the RBC, the antibodies agglutinate which is detected as “clumping”.

48
Q

What is the indirect Coombs test?

What is the utility of it?

A

The pt.’s serum is tested for its ability to agglutinate commercially available RBCs bearing certain antigens.

It is used to characterize the antigen target and temperature dependence of the responsible antibody.

49
Q

What is the most common cause of hemolytic anemia due to trauma to red cells? Why?

A

Patients with cardiac valve prostheses and microangiopathic disorders. It causes changes in turbulent flow and pressure gradients, which damages the RBCs.

50
Q

Microangiopathic hemolytic anemia is most commonly seen in which disorder?

A

DIC, but may also happen with TTP, HUS, malignant HTN, SLE and disseminated cancer.

51
Q

What are schistocytes?

When might they be seen?

A

Red cell fragments (“Burr cells”, “helmet cells”, etc.).

Hemolytic anemia due to trauma of RBCs.

52
Q

What is the inheritance of the thalassemias?

A

Autosomal codominance

53
Q

What is the most important cause of anemias of diminished erythropoiesis?

A

Nutritional deficiencies

54
Q

What is deficient in megaloblastic anemias?

What symptoms may suggest this type of anemia?

A

Vit. B12, folic acid or thymidine.

Neurologica symptoms - paraparesis, sensory ataxia and parasthesias of the LE.

55
Q

What is pernicious anemia? What is the disease association?

The diagnosis is based on what 4 findings?

When does reticulocytosis and rising Hct. begin after giving vitamin B12?

A

It is a subtype of megaloblastic anemia caused by impaired intrinsic factor (IF) production, which is needed for vit. B12 uptake. It is associated with autoimmune gastritis.

  1. Moderate to severe megaloblastic anemia.
  2. Leukopenia w/ hypersegmented graulocytes.
  3. Low serum vit. B12.
  4. Elevated homocytseine and methymalonic acid.

About 5 days after administration of vit. B12.

56
Q

In pernicious anemia, what triggers the formation of autoantibodies?

A

An autoreactive T-cell response initiates gastric mucosa injury and the formation of autoantibodies.

57
Q

What is the ferritin concentration in iron deficiency anemia (IDA)?

What is the most common cause of IDA in the Western world?

A

<12 ug/L.

Chronic blood loss.

58
Q

IDA in men and post-menopausal women in the Western world should be ascribed to what until proven otherwise?

A

Occult blood loss, often in the GI tract.

59
Q

What is the appearance of red cells in IDA?

What are the concentrations of the following?
Hct.
Hb
[Iron]
[Ferritin]
[Total iron binding capacity (TIBC)]
[Hepcidin]
A

Microcytic, hypochromic anemia with mild poikilocytosis.

Hct.: low
Hb: low
[Iron]: low
[Ferritin]: low
[Total iron binding capacity (TIBC)]: high
[Hepcidin]: low
60
Q

What is the most common type of anemia in hospitalized patients in the US?

What are its 3 major categories in this setting?

A

Anemia of chronic disease.

Chronic infection
Chronic autoimmune disorders
Neoplasms - bronchogenic carcinoma, Hodgkin lymphoma, etc.

61
Q

How does chronic inflammation lead to anemia of chronic disease?

How is it diagnosed? (2)

A

It activated cytokines and mediators which suppress erythropoisis by stimulation hepcidin, thus blocking the transfer of iron to erythroid precursors.

Elevated [ferritin]
Low [TIBC] ([TIBC] is high in IDA).

62
Q

What is the most common cause of aplastic anemia (65% of cases)?

What unique feature does it exhibit?

What 2 major mechanisms are believed to be involved in the majority of cases?

What is needed for biopsy?

A

Idiopathic

Pancytopenia

(1) Extrinsic, immune-mediated suppression of marrow precursors.
(2) Stem-cell abnormalities.

Bone marrow biopsy is needed.

63
Q

What are the clinical features of aplastic anemia?

What is the prognosis?

A

It is insidious in onset and shows features os=f anemia, with possible ecchymosis/petechiae (thrombocytopenia) and infections (neutropenia). It is important to exclude other causes of pancytopenia.

It is variable. It usually required BM transplant or immunosuppressive therapy.

64
Q

What etiologies may cause pure red cell aplasia? (5)

What is the theme of these causes?

A
Thymoma - resection of thymus leads to improvement in half of patients.
Large, granular lymphocytic leukemia
Some drugs
Autoimmune disorders
Parvovirus B19 infection

With the exception of parvovirus infection, most seem to have an autoimmune etiology.

65
Q

Which malignancies (aside form lymphomas/leukemias) may manifest as marrow failure? (3)

What chronic diseases (aside from hematologic diseases) can manifest as marrow failure

A

Breast, lung and prostate carcinomas.

Renal failure, hepatocellular liver failure and endocrine disorders.

66
Q

How can primary and secondary polycythemia be differentiated?

A

Primary - low EPO (i.e. PV).

Secondary - high EPO.