Hemolytic Anemias Part 2

Question 1

Thalassemia Syndromes

Answer 1

The thalassemia syndromes are a heterogeneous group of disorders caused by inherited mutations that decrease the synthesis of either the α-globin or β-globin chains that compose adult hemoglobin, HbA (α2β2), leading to anemia, tissue hypoxia, and red cell hemolysis related to the * imbalance in globin chain synthesis.*

Question 2

Hemoglobin molecule

Answer 2

Hemoglobin A – Tetramer of 4 globin chains + 4 heme

Question 3

β-Thalassemias

Answer 3

The β-thalassemias are caused by mutations that diminish the synthesis of β-globin chains

β0 mutations, associated with absent β-globin synthesis
β+ mutations, characterized by reduced (but detectable) β-globin synthesis

Question 4

β-Thalassemias

Peripheral blood smear

Answer 4

Impaired β-globin synthesis results in anemia by two mechanisms.
The deficit in HbA synthesis produces *“underhemoglobinized” hypochromic, microcytic red cells with subnormal oxygen transport capacity.
Even more important is the diminished survival of red cells and their precursors, which results from the imbalance in α- and β-globin synthesis.

Question 5

severe β-thalassemia

Answer 5

it is estimated that * 70% to 85% of red cell precursors suffer diminished survival, which leads to * ineffective erythropoiesis. Those red cells that are released from the marrow also bear inclusions and membrane damage and are prone to splenic sequestration and * extravascular hemolysis.

Question 6

β-Thalassemia Major

Answer 6

The anemia manifests 6 to 9 months after birth as hemoglobin synthesis switches from HbF to HbA.
In untransfused patients, hemoglobin levels are 3 to 6 gm/dL

Anisocytosis

Poikilocytosis

Microcytosis

Hypochromia

Question 7

β-Thalassemia Minor

Answer 7

These patients are usually *asymptomatic. Anemia, if present, is mild. The peripheral blood smear typically shows some red cell abnormalities, including hypochromia, microcytosis, basophilic stippling, and target cells.

Hemoglobin electrophoresis usually reveals an increase in * HbA2 (α2δ2) to 4% to 8% of the total hemoglobin (normal, 2.5% ± 0.3%), which is a reflection of an elevated ratio of δ-chain to β-chain synthesis.

Question 8

Recognition of β-thalassemia trait is important for two reasons:

Answer 8

It superficially *resembles the hypochromic microcytic anemia of iron deficiency

It has implications for *genetic counseling. Iron deficiency can usually be excluded through measurement of serum iron, total iron-binding capacity, and serum ferritin

Question 9

old male with iron deficiency anemia is what until proven otherwise?

Answer 9

colon cancer

Question 10

an anemia that doesnt get better with iron is what until proven otherwise?

Answer 10

thalassemia beta minor

Question 11

The α-thalassemias are caused by

Answer 11

inherited deletions that result in reduced or absent synthesis of α-globin chains

Question 12

Alpha Thalassemia Clinical Syndromes

Answer 12

Loss one gene: diminishes the production of the alpha globin
protein slightly and patient is “normal” - Silent Carrier.

2. Loss of two genes: Clinically asymptomatic but microcytic red cells, and at most a mild anemia– Alpha thalassemia Trait.
3. Loss three genes: Severe anemia, requiring RBC transfusion to survive. Untreated patients die childhood/early adolescence.With three-gene deletion in alpha thalassemia, beta chains (in great excess) begin to associate in tetramers, producing an abnormal hemoglobin, “Hemoglobin H” Disease.
4. Loss four genes: Incompatible with life – Hydrops Fetalis

Question 13

golf ball inclusions are?

Answer 13

hemoglobin H, a 3 gene deletion

Question 14

What happens in hydrops fatalis

Answer 14

hemoglobin hangs onto the oxygen, baby dies of hypoxia

Question 15

red cells missing CD 59 and CD55

Answer 15

those things keep complement from lysing your RBCs

makes them susceptible when they’re missing

Question 16

Paroxysmal Nocturnal Hemoglobinuria

Answer 16

Paroxysmal nocturnal hemoglobinuria (PNH) is a disease that results from * acquired mutations in the phospha­tidylinositol glycan complementation group A gene (PIGA), an enzyme that is essential for the synthesis of certain membrane-associated complement regulatory proteins.

Red cells deficient in these GPI-linked factors are abnormally susceptible to lysis or injury by complement

at night pH changes

Question 17

PNH blood cells are deficient in three GPI-linked proteins that regulate complement activity:

Answer 17

Decay-accelerating factor or CD55
Membrane inhibitor of reactive lysis, or CD59
C8 binding protein

Question 18

Paroxysmal Nocturnal Hemoglobinuria

manifests as

Answer 18

• intravascular hemolysis, which is caused by the C5b-C9 membrane attack complex.

The hemolysis is * paroxysmal and nocturnal in only 25% of cases; chronic hemolysis without dramatic hemoglobinuria is more typical. The tendency for red cells to lyse at night is explained by a slight decrease in blood pH during sleep, which increases the activity of complement.

The anemia is variable but usually mild to moderate in severity. The loss of heme iron in the urine * (hemosiderinuria) eventually leads to iron deficiency, which can exacerbate the anemia if untreated

Question 19

leading cause of disease related death in individuals with PNH:

and other complications that arise

Answer 19

Thrombosis.

About 40% of patients suffer from venous thrombosis, often involving the hepatic, portal, or cerebral veins.

About 5% to 10% of patients eventually develop acute myeloid leukemia or a myelodysplastic syndrome, possibly because hematopoietic stem cells have suffered some type of genetic damage.

Question 20

PNH is diagnosed by … and treated with …

Answer 20

flow cytometry, which provides a sensitive means for detecting red cells that are deficient in GPI-linked proteins such as CD59.

The cardinal role of complement activation in PNH pathogenesis has been proven by therapeutic use of a monoclonal antibody called Eculizumab that prevents the conversion of C5 to C5a.

This inhibitor not only reduces the hemolysis and attendant transfusion requirements, but also lowers the risk of thrombosis by up to 90%

Question 21

Only acquired hemolytic anemia

Answer 21

PNH

Question 22

Direct antiglobulin test

Answer 22

= coombs test

antibodies are on the patient’s red cell and –> agglutination

Question 23

Immunohemolytic Anemias are

caused by

Answer 23

antibodies that bind to red cells, leading to their premature destruction

Commonly referred to as autoimmune hemolytic anemias

Question 24

warm antibody type

Answer 24

igG
primary (idiopathic)
secondary– autoimmune disorder, drugs, lymphoid neoplasms

About 50% of cases are idiopathic (primary); the others are related to a predisposing condition or exposure to a drug.

Most causative antibodies are of the IgG class

Extremely difficult to treat since patient has antibody against their own reds blood cells. This autoantibody also reacts with all other human red cells……… THERE IS NO COMPATIBLE BLOOD FOR TRANSFUSION

Question 25

Cold agglutinin type

Answer 25

IgM

acute (mycoplasmal infection, infectious mono)
Chronic- idiopathic, lymphoid neoplasms

Caused by IgM antibodies that bind red cells avidly at low temperatures (0°C to 4°C)

Appear transiently following certain infections, such as with Mycoplasma pneumoniae, Epstein-Barr virus, cytomegalovirus, influenza virus, and human immunodeficiency virus (HIV)

Clinical symptoms result from binding of IgM to red cells in vascular beds where the temperature may fall below 30°C, such as in exposed fingers, toes, and ears

Also seen with CLL***

Question 26

Cold hemolysin type (of IgG)

Answer 26

IgG antibodies active below 37 degrees)

rare; occurs mainly in children following viral infections

Question 27

Mechanisms of drug-induced immunohemolytic anemia : antigenic drugs

Answer 27

In this setting hemolysis usually follows large, intravenous doses of the offending drug and occurs 1 to 2 weeks after therapy is initiated. These drugs, exemplified by penicillin and cephalosporins, bind to the red cell membrane and are recognized by antidrug antibodies.

Question 28

Mechanisms of drug-induced immunohemolytic anemia :

Tolerance-breaking drugs

Answer 28

These drugs, of which the antihypertensive agent α-methyldopa is the prototype, induce in some unknown manner the production of antibodies against red cell antigens, particularly the Rh blood group antigens.

Question 29

About 10% of patients taking α-methyldopa develop

Answer 29

autoantibodies, as assessed by the direct Coombs test, and roughly 1% develop clinically significant hemolysis.

Question 30

Cold Hemolysin Type (of IgG)

Answer 30

Autoantibodies responsible for an unusual entity known as paroxysmal cold hemoglobinuria

The autoantibodies are IgGs that bind to the P blood group antigen on the red cell surface in cool, peripheral regions of the body. Complement-mediated lysis occurs when the cells recirculate to warm central regions, because the complement cascade functions more efficiently at 37°C.

Most cases are seen in children following viral infections; in this setting the disorder is transient, and most of those affected recover within 1 month.

Question 31

Hemolytic Anemia Resulting from Trauma to Red Cells: cardiac valves

Answer 31

The most significant hemolysis caused by trauma to red cells is seen in individuals with cardiac valve prostheses and microangiopathic disorders

Artificial mechanical cardiac valves are more frequently implicated than are bioprosthetic porcine or bovine valves.

The hemolysis stems from shear forces produced by turbulent blood flow and pressure gradients across damaged valves

Question 32

Hemolytic Anemia Resulting from Trauma to Red Cells:

Microangiopathic hemolytic anemia

Answer 32

is most commonly seen with disseminated intravascular coagulation, but it also occurs in thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), malignant hypertension, systemic lupus erythematosus, and disseminated cancer

The common pathogenic feature in these disorders is a microvascular lesion that results in luminal narrowing, often due to the deposition of fibrin and platelets

Regardless of the cause, traumatic damage leads to the appearance of red cell fragments (schistocytes), “burr cells,” “helmet cells,” and “triangle cells” in blood smears