Membranopathies

Question 1

The lipid bilayer comprises approximately _____% of the membrane mass

Answer 1

50%

Contains unesterified cholesterol and phospholipids in approximately equal amounts, with small amounts of glycolipids and phosphoinositides

Question 2

TRUE OR FALSE

Mature erythrocytes are unable to synthesize fatty acids, phospholipids, or cholesterol de novo, and they depend on lipid exchange and limited phospholipid repair.

Answer 2

TRUE

Mature erythrocytes are unable to synthesize fatty acids, phospholipids, or cholesterol de novo, and they depend on lipid exchange and limited phospholipid repair.

Question 3

lt regulates the fluidity of the membrane and is present in both leaflets

Answer 3

Cholesterol

Phospholipids are asymmetrically distributed

Question 4

Located in the outer leaflet and play a role in plasma lipid exchange and renewal of membrane phospholipids

Answer 4

Phosphatidylcholine and sphingomyelin

choline phospholipids

Question 5

Location in the lipid bilayer

Red cell antigens (A, B, H, and P): ________
Aminophospholipids: phosphatidylserine and phosphatidylethanolamine: ___________

Answer 5

Red cell antigens (A, B, H, and P): EXTERNAL

Aminophospholipids: phosphatidylserine and phosphatidylethanolamine: INTERNAL

Question 6

The asymmetric distribution of phospholipids is maintained by a dynamic process involving ________that translocate the aminophospholipids to the inner and outer leaflets, respectively

Answer 6

Flippase (ATP11C) and Floppase enzymes

A missense mutation in the ATP11C gene on the X chromosome causes mild hemolytic anemia.

Question 7

Asymmetry of the phospholipids is important for the survival of the erythrocyte because exposure of _________on the cell surface, as found in sickle cell disease and thalassemia, has several deleterious consequences

Answer 7

Phosphatidylserine

• It activates the coagulation cascade and may contribute to thromboses;
• it facilitates adhesion to the vascular endothelium;
• it provides a recognition signal for macrophages to phagocytose these cells; and
• it decreases the interaction of skeletal proteins with the bilayer, which destabilizes the membrane.

Question 8

A calcium-dependent enzyme that mediates ATP-independent bidirectional movement of phospholipids down their concentration gradient and contributes to the maintenance of phosphatidylserine on the inner leaflet of the membrane.

Answer 8

Scramblase (PLSCR1)

Question 9

Lipid rafts are anchored to ________ and play a role in signaling and invasion of malaria parasites

Associated with several proteins, including stomatin, flotillin-1 and flotillin-2.

Answer 9

Spectrin

Question 10

2 classifications of membane proteins:

Answer 10

• Integral
• Peripheral

Question 11

Embedded in the lipid bilayer, functions as transport proteins, receptors, signaling molecules, and carriers of red cell antigens

Require detergents to extract them

Answer 11

Integral or transmembrane proteins

Question 12

Constitute the membrane skeleton and are loosely attached to the cytoplasmic face of the lipid bilayer and can be extracted by high or low salt concentrations or by high pH

Function either as structural proteins and form part of the membrane skeleton or they serve as linker proteins attaching the skeleton to the bilayer

Answer 12

Peripheral proteins

Question 13

The most abundant and important erythrocyte transmembrane proteins

Answer 13

• Anion exchanger-1 (AE1)
• Glycophorins (GPs)

Other Integral Membrane Proteins:
* Rh-RhAG group of proteins
* Ion pumps and channels: omatin, aquaporin, glucose transporter-1 (GLUT-1)
* Cation and anion transporters

Question 14

Encompasses 13 α-helical transmembrane segments and 1 nonhelicalsegment, all connected by hydrophilic loops.

Answer 14

Anion exchanger-1 (AE1)

• The short cytoplasmic tail binds cytosolic carbonic anhydrase II to form a metabolon with the transmembrane domain, enabling the exchange of HCO3− and Cl− anions
• The external surface of the transmembrane domain of AE1 carries several antigens, including Diego, I/i, and Wright blood groups.
• The N-terminal phosphorylated cytoplasmic domain serves as a major hub for protein-protein interactions; serves as the primary anchor of the glycolytic enzymemetabolon.
• Serves as the major attachment site of the membrane to the underlying skeleton through its interaction with ankyrin, which binds to spectrin

Question 15

Gene ecoding anion exchanger-1 (AE1)

Answer 15

SLC4A1 gene previously known as band 3

The erythroid isoform is controlled by a promoter upstream of exon 1, whereas transcription of the kidney isoform is initiated from a promoter in intron 3

Question 16

Responsible for most of the external negative charge of red cells glycophorins, which prevents the adherence of cells to each other and the vascular endothelium

Answer 16

Sialic acid

Question 17

Function as receptors for Plasmodium falciparum, the most virulent malaria parasite

Answer 17

Glycophorins

• Carry a large number of blood group antigens, including MN, SsU, Miltenberger, En(a−), MK, and Gerbich
• GPA interacts with AE1 as part of a macromolecular complex
• GPC associates with protein 4.1R and p55, thereby providing an additional contact site between the membrane and the skeleton.

Question 18

Plays a critical role in maintaining the shape and integrity of the red cell

Answer 18

Peripheral Membrane Proteins

SAAAP-iiinnnn

spectrin, actin, adducin, ankyrin, proteins 4.1R, 4.2, 4.9, p55

Question 19

Major proteins of the erythrocyte membrane skeleton which interact in a horizontal plane

Answer 19

Spectrin, actin, proteins 4.1R, 4.2, 4.9, p55, and the adducins

Question 20

Mediate the vertical attachment of the skeleton to integral membrane proteins in the lipid bilayer

Answer 20

Linker proteins
* Ankyrin
* Protein 4.1R

Question 21

The primary connecting protein which links β- spectrin to the cytoplasmic domain of AE1, as well as to the Rh/RhAG complex

Answer 21

Ankyrin

Protein 4.1R binds to GPC and AE1, which serves as a secondary attachment site of the skeleton to integral membrane proteins

Question 22

Major constituent of the erythrocyte membrane skeleton

Answer 22

Spectrin

Question 23

Provides the red cell with elasticity and durability to withstand the shear stress encountered in the circulation

Other functions:
* Maintain the biconcave disk shape of the red cell
* Regulate the lateral mobility of integral membrane proteins, and
* Provide structural support for the lipid bilayer

Answer 23

Spectrin

Composed of 2 homologous, but structurally distinct, subunits, α and β, encoded by separate genes, SPTA1 and SPTB, respectively

Question 24

Behaves like a reversible spring, which may contribute to the elasticity of the membrane

Answer 24

Ankyrin

• Bind to AE1 and the Rh–RhAG macromolecular complex
• Encoded by the ANK1 gene

Question 25

Responsible for binding to the cytoplasmic domains of **AE1** and **GPC**, as well as to **p55**, thereby linking the skeleton to the lipid bilayer

Answer 25

Protein 4.1R ## Footnote Encoded by EPB41

Question 26

Form of protein 4.1R that is predominating in **young erythrocytes** ## Footnote Two forms of protein 4.1R, a and b

Answer 26

Protein 4.1b

Question 27

A member of the transglutaminase family of proteins, but it has **no enzyme activity** because it lacks the critical triad of residues that form the active transglutaminase site

Answer 27

Protein 4.2

Question 28

A **calcium/calmodulin-binding phosphoprotein** located at the spectrin–actin junctional complex Also bind AE1 and GLUT-1, and thus form part of the macromolecular junctional complex linking the spectrin skeleton to the lipid bilaye

Answer 28

Adducin

Question 29

A trimeric phosphoprotein that acts as a linker molecule by binding to the transmembrane GLUT-1

Answer 29

Dematin or protein 4.9

Question 30

Composition of the **ankyrin complex**

Answer 30

AE1, GPA, Rh, and RhAG complex proteins Ankyrin, protein 4.2, and several glycolytic enzymes

Question 31

Composition of the **distal junctional complex**

Answer 31

AE1, GPC, GLUT-1, Rh, Kell, and XK proteins Proteins 4.1R, actin, dematin, adducin, tropomyosin, tropomodulin, and p55.5

Question 32

The membrane skeleton resembles a lattice-like network, with approximately ______% of the lipid bilayer directly laminated to the underlying skeleton

Answer 32

60%

Question 33

The (horizontal or vertical) protein interactions are important in the maintenance of the **structural integrity** of the cell, accounting for the high tensile strength of the erythrocyte

Answer 33

Horizontal

Question 34

The (horizontal or vertical) protein–protein interactions are critical in the **stabilization of the lipid bilayer**, **preventing loss of microvesicles** from the cells

Answer 34

Vertical

Question 35

Average life span of RBCs

Answer 35

120 days

Question 36

3 features that regulate the deformability of RBCs:

Answer 36

(a) the biconcave disk shape (a high ratio of surface area to cellular volume) (b) the viscoelastic properties of the membrane (spectrin) (c) the cytoplasmic viscosity

Question 37

Characteristic of RBC that provides a **high ratio of surface area to cellular volume** and this excess of membrane is critical for survival of the cell

Answer 37

Biconcave disk shape ## Footnote To prevent fragmentation of the membrane and loss of the biconcave disk shape, the structural integrity of the membrane skeleton is critical. The horizontal interactions of the peripheral proteins of the **junctional complex, mainly protein 4.1R and actin**, which link the tail ends of the spectrin tetramers together, is a major determinant of membrane stability.

Question 38

**Cytoplasmic viscosity** is determined primarily by the ____________

Answer 38

Intracellular hemoglobin concentration

Question 39

As the **mean cell hemoglobin concentration** rises above _________, the viscosity increases exponentially

Answer 39

370 g/L

Question 40

The hemoglobin concentration is critically dependent on red cell volume, which is primarily determined by the ___________

Answer 40

Total cation content of the cell

Question 41

The red cell membrane maintains a _______ potassium, ________ sodium, and________calcium content within the cell.

Answer 41

High potassium Low sodium Very-low calcium

Question 42

Extrudes 3 sodium ions in exchange for 2 potassium ions entering the red cell

Answer 42

Na+K+ ATPase

Question 43

Calcium is pumped out of the cell by this channel Protects the cell from deleterious effects of calcium, such as echinocytosis, membrane vesiculation, calpain activation, membrane proteolysis, and cellular dehydration

Answer 43

Calmodulin-activated Ca2+ ATPase

Question 44

The Ca2+-activated K+ channel, also called the _____________ It causes selective loss of K+ in response to increased intracellular Ca2+

Answer 44

Gardos channel

Question 45

Chloride and bicarbonate anions are readily exchanged through ____

Answer 45

AE1

Question 46

Water is transported by

Answer 46

Aquaporin-1 (AQP1)

Question 47

# Vertical or Horizontal proteins Result in **destabilization** of the bilayer, **loss of membrane microvesicles** and **spherocyte formation**

Answer 47

Vertical

Question 48

# Vertical or Horizontal proteins Disrupt the skeleton resulting in **defective shape recovery** and **elliptocytes**

Answer 48

Horizontal

Question 49

The most common cause of HE and HPP

Answer 49

Functional self-association defect in α-Spectrin

Question 50

Protein defect that cause **“Acanthocytic” spherocytes** present on blood film presplenectomy

Answer 50

β-Spectrin

Question 51

Deficiency of _________ is the most common cause of **HS in North America**

Answer 51

Ankyrin

Question 52

Deficiency is the most common cause of **HS in parts of Europe and South Africa** **“Pincered” spherocytes** are common on blood film presplenectomy

Answer 52

AE1

Question 53

Deficiency primarily found in **Japanese** patients with HS

Answer 53

Protein 4.2 ## Footnote The most common mutation is **protein 4.2 Nippon**, and patients may be homozygous for this mutation or compound heterozygotes with a second mutation on the other allele.

Question 54

Protein defect in **Ankyrin** and **Protein 4.2** cause

Answer 54

HS recessive ## Footnote The stabilizing effect of the transmembrane section of AE1 on the lipid bilayer is lost, facilitating the formation of AE1-free microvesicles

Question 55

**SAO** is caused by defect in what protein

Answer 55

AE1

Question 56

Defect in this protein cause **spiculated cells (acanthocytes and echinocytes)** in addition to spherocytes. Autosomal dominant HS

Answer 56

Beta spectrin

Question 57

Defect in this protein cause "pincered" spherocytes

Answer 57

AE1

Question 58

The hallmark of HS erythrocytes

Answer 58

Loss of membrane surface area relative to intracellular volume

Question 59

# TRUE OR FALSE The spleen plays a secondary, but important, role in the pathophysiology of HS.

Answer 59

TRUE The spleen plays a secondary, but important, role in the pathophysiology of HS. ## Footnote Spherocytes are retained and ultimately destroyed in the spleen and this is the primary cause of the chronic hemolysis experienced by HS patients *The degree of splenic retention correlated with the reduction in the surface-area-to-volume ratio.*

Question 60

In approximately **75%** of HS patients, inheritance is _________________

Answer 60

Autosomal dominant

Question 61

Mutations of these genes are associated with **recessive HS**

Answer 61

α-spectrin or protein 4.2

Question 62

Approximately _________ of HS patients have **moderate disease**

Answer 62

60% to 70%

Question 63

The most frequent finding (50% of cases) of HS among children ## Footnote No comparable data exist for adults.

Answer 63

Anemia ## Footnote Followed by splenomegaly, jaundice, or a positive family history

Question 64

# TRUE OR FALSE Jaundice may be intermittent and is seen in approximately half of patients, usually in association with viral infections

Answer 64

TRUE **Jaundice** may be **intermittent** and is seen in approximately **half** of patients, usually in association with viral infections ## Footnote When present, jaundice is **acholuric**, characterized by **unconjugated hyperbilirubinemia without detectable bilirubinuria**.

Question 65

Palpable splenomegaly is evident in most (>_____%) older children and adults.

Answer 65

>75% ## Footnote *No proven correlation exists between the spleen size and the severity of HS.*

Question 66

Approximately 20% to 30% of HS Splenomegaly is mild, reticulocyte counts are generally **less than 6%**, and spherocytes on the blood film may be minimal ## Footnote Bilirubin 1-2 Inherritance: Autosomal dominant

Answer 66

Mild Hereditary Spherocytosis

Question 67

Approximately________ of HS patients have **moderately severe disease**, as evidenced by indicators of anemia that are more pronounced than in typical moderate HS, and an intermittent requirement for transfusions ## Footnote Bilirubin 2-3 Inherritance: Autosomal dominant; de novo

Answer 67

5% to 10%

Question 68

A small number (________%) of patients have **severe** disease with **life-threatening anemia** and are **transfusion dependent**.

Answer 68

<5% ## Footnote * They almost always have **recessive HS**. * Most have severe **spectrin** deficiency; defects in ankyrin or AE1 have also been identified

Question 69

Characteristics of patients with severe HS

Answer 69

* Recessive HS * Severe spectrin deficiency (α-spectrin) * Irregularly contoured or budding spherocytes or bizarre poikilocytes

Question 70

Most common finding in **neonates with HS**

Answer 70

Jaundice ## Footnote It may be accentuated by coinheritance of **Gilbert syndrome**, caused by homozygosity for a polymorphism in the promoter of the UGT1 gene

Question 71

Most frequently reported complication in as many as half of HS patients

Answer 71

Bilirubinate gallstones ## Footnote Coinheritance of Gilbert syndrome markedly increases the risk of gallstone formation.

Question 72

The **most common crisis in HS**, which is usually associated with **viral illnesses**. Generally mild and characterized by jaundice, splenomegaly, anemia, and reticulocytosis

Answer 72

Hemolytic crisis ## Footnote Others: Aplastic crises Megaloblastic crises

Question 73

The most common etiologic agent in aplastic crisis

Answer 73

Parvovirus ## Footnote Aplastic crises usually last for **10–14 days** and may bring asymptomatic, undiagnosed HS patients with compensated hemolysis to medical attention

Question 74

May occur in HS patients with **increased folate demands**, such as pregnant patients, growing children, or patients recovering from an aplastic crisis

Answer 74

Megaloblastic crises

Question 75

# TRUE OR FALSE Leg ulcers, chronic dermatitis on the legs and gout are rare manifestations of HS, which usually do not heal even after splenectomy.

Answer 75

FALSE **Leg ulcers, chronic dermatitis on the legs and gout** are **rare** manifestations of HS, which usually **heal rapidly after splenectomy.**

Question 76

Most patients have mild to moderate anemia with hemoglobin in the _________range

Answer 76

90–120 g/L

Question 77

# TRUE OR FALSE Mean corpuscular volume is increased because of relative cellular dehydration in approximately half of patients, but all HS patients have some hydrated cells

Answer 77

FALSE **Mean corpuscular hemoglobin concentration (MCHC)** is increased **(>36 g/dL)** because of relative cellular dehydration in approximately half of patients, but all HS patients have some dehydrated cells ## Footnote Can be useful as a screening test for HS, especially when combined with an increased red cell distribution width.

Question 78

# TRUE OR FALSE Mean corpuscular volume (MCV) is usually normal except in cases of severe HS, when MCV is slightly decreased.

Answer 78

TRUE **Mean corpuscular volume (MCV)** is usually **normal** except in cases of severe HS, when MCV is slightly **decreased**.

Question 79

Markers of hemolysis

Answer 79

* Reticulocytosis * Increased lactate dehydrogenase * Increased urinary and fecal urobilinogen * Unconjugated hyperbilirubinemia * Decreased serum haptoglobin

Question 80

# TRUE OR FALSE Spherocytes typically swell and burst at lower sodium chloride concentrations than do normal biconcave disk-shaped red cells.

Answer 80

FALSE Spherocytes typically **swell and burst** at **HIGHER** sodium chloride concentrations than do normal biconcave disk-shaped red cells.

Question 81

Tests for hemolysis with poor sensitivity and do not detect all cases of mild HS or those with small numbers of spherocytes, including patients who had recent blood transfusions.

Answer 81

Glycerol lysis test and the acidified glycerol lysis test ## Footnote * Unreliable and give normal results in the presence of iron deficiency, obstructive jaundice, or, during the recovery phase, of an aplastic crisis * Do not differentiate HS from other disorders with secondary spherocytosis

Question 82

A fluorescent dye that binds to the transmembrane proteins, AE1, Rh protein, Rh glycoprotein, and CD47

Answer 82

Eosin 5′-maleimide (EMA)

Question 83

Expected finding of HS in Eosin 5′-Maleimide Flow Cytometry Test

Answer 83

Decreased fluorescence compared to controls ## Footnote Also may be observed in patients with HE, HPP, some red cell enzymopathies, and other abnormalities of AE1, such as congenital dyserythropoietic anemia type II (CDAII)

Question 84

This useful test monitors red cell deformability under a continuous osmotic gradient and a known shear stress, which generates a **deformability index profile**.

Answer 84

Osmotic Gradient Ektacytometry

Question 85

Expected finding of HS in Osmotic Gradient Ektacytometry

Answer 85

Decreased maximum deformability index combined with an increased minimum osmotic (Omin) gradient

Question 86

This test identifies the underlying **defective protein** after separation of the red cell membrane proteins

Answer 86

Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis SDS-PAGE

Question 87

# TRUE OR FALSE All the laboratories used at least 2 tests to make a final diagnosis of HS, as none of the currently available methods have 100% sensitivity.

Answer 87

TRUE All the laboratories used at least **2 tests** to make a final diagnosis of HS, as none of the currently available methods have 100% sensitivity.

Question 88

In neonatal HS, HS ratio (MCHC divided by MCV) of greater than_______has a very high sensitivity and specificity

Answer 88

0.36

Question 89

The primary **determinant of erythrocyte survival** in HS patients

Answer 89

Splenic sequestration

Question 90

# TRUE OR FALSE Postsplenectomy, spherocytosis, and altered osmotic fragility persist, but the “tail” of the osmotic fragility curve, created by conditioning of a subpopulation of spherocytes by the spleen, disappears.

Answer 90

TRUE Postsplenectomy, **spherocytosis, and altered osmotic fragility persist**, but the*"tail” of the osmotic fragility curve, created by conditioning of a subpopulation of spherocytes by the spleen, disappears.*

Question 91

HS patients candidate for splenectomy

Answer 91

- Transfusion-dependent severe spherocytosis - Significant signs or symptoms of anemia: growth failure, skeletal changes, leg ulcers, and extramedullary hematopoietic tumors - patients suffering from vascular compromise of vital organs ## Footnote **Laparoscopic splenectomy** has become the method of choice

Question 92

Because the risk of postsplenectomy sepsis is very high during infancy and early childhood, splenectomy should be delayed until age ______ years if possible and to at least ______years if feasible

Answer 92

5 to 9 years 3 years

Question 93

Postsplenectomy prophylactic antibiotics

Answer 93

* Penicillin V 125 mg orally twice daily for patients younger than 7 years or * Penicillin V 250 mg orally twice daily for those older than 7 years, including adults ## Footnote For at least **5 years** postsplenectomy by some and **for life** by others

Question 94

Presplenectomy and, in severe cases, post-splenectomy, HS patients should take folic acid (______mg/day orally) to prevent folate deficiency.

Answer 94

Folic acid (1 mg/day orally)

Question 95

Reasons for splenectomy failure:

Answer 95

* Missed accessory spleen * Development of splenunculi as a consequence of autotransplantation of splenic tissue during surgery * Another intrinsic red cell defect, such as pyruvate kinase deficiency

Question 96

Accessory spleens occur in ____% to ____% of patients and must always be sought.

Answer 96

15% to 40%

Question 97

Definitive confirmation of ectopic splenic tissue

Answer 97

Radiocolloid liver– spleen scan or Scan using 51Cr-labeled, heat-damaged red cells

Question 98

Characterized by the presence of **elliptical** or **oval** erythrocytes on the blood films

Answer 98

HEREDITARY ELLIPTOCYTOSIS

Question 99

The erythrocytes from these patients exhibited **increased thermal sensitivity**. Seen in patients suffering from **severe burns**

Answer 99

HEREDITARY PYROPOIKILOCYTOSIS

Question 100

The primary abnormality in HE erythrocytes

Answer 100

Defective **HORIZONTAL** interactions between components of the membrane skeleton

Question 101

The most common defects in HE and HPP

Answer 101

Spectrin ## Footnote Mutations that affect spectrin heterodimer self-association are found in the **majority of HE** patients and in **all patients with HPP**. This functional defect results in an **increased percentage of spectrin dimers** relative to tetramers

Question 102

The primary abnormality in HPP erythrocytes

Answer 102

Combination of **HORIZONTAL** (impaired spectrin tetramer formation) and **VERTICAL** (spectrin deficiency) defects

Question 103

The most important determinants of the severity of hemolysis in HE

Answer 103

Percentage of spectrin dimers and the spectrin content of the membrane skeleton

Question 104

The most common polymorphism affecting spectrin content and clinical severity

Answer 104

αLELY, the low-expression Lyon α-spectrin allele

Question 105

HE is typically inherited as an _________ disorder.

Answer 105

Autosomal dominant

Question 106

# TRUE OR FALSE HPP is an autosomal recessive disorder and a strong genetic relationship exists between HE and HPP, whereby parents or siblings of patients with HPP often have typical HE.

Answer 106

TRUE **HPP** is an **autosomal recessive** disorder and a strong genetic relationship exists between HE and HPP, whereby parents or siblings of patients with HPP often have typical HE.

Question 107

# TRUE OR FALSE (Clinical presentation) The overwhelming majority of patients with HPP are asymptomatic and are diagnosed incidentally HE patients present in infancy or early childhood with severe hemolytic anemia

Answer 107

FALSE The overwhelming majority of patients with **HE** are **asymptomatic** and are diagnosed incidentally **HPP** patients present in infancy or early childhood with **severe hemolytic anemia**

Question 108

# Hereditary Elliptocytosis and Pyropoikilocytosis in Infancy Typically, elliptocytes do not appear on the blood film until the patient is _________

Answer 108

4–6 months old ## Footnote * These patients may require red cell transfusion, phototherapy, or exchange transfusion. * Usually, even in severely affected patients, the hemolysis abates between **9 and 12 months** of age, and the patient progresses to typical HE with mild anemia.

Question 109

The hallmark of HE

Answer 109

Presence of cigar-shaped elliptocytes on blood films

Question 110

# TRUE OR FALSE The degree of hemolysis does not correlate with the number of elliptocytes present.

Answer 110

TRUE *The degree of hemolysis does not correlate with the number of elliptocytes present.*

Question 111

Blood smear features of HPP

Answer 111

**Extreme poikilocytosis**, some bizarre-shaped cells with fragmentation or budding, and often only very few or no elliptocytes ## Footnote **Microspherocytosis** is common and MCV is usually low, ranging between 50 fL and 70 fL. *The **thermal instability** of erythrocytes, originally reported as diagnostic of HPP, is **not unique to this disorder** as it is also commonly found in HE erythrocytes.*

Question 112

Prominent cells on blood films of neonates with HPP

Answer 112

Pyknocytes

Question 113

Causes of acquired elliptocytosis

Answer 113

Megaloblastic anemias, hypochromic microcytic anemias (iron-deficiency anemia and thalassemia), myelodysplastic syndromes, and myelofibrosis

Question 114

Acquired elliptocytosis generally represents less than _______ of red cells seen on the blood film.

Answer 114

25%

Question 115

An artifact of blood film preparation and these cells are found only in certain areas of the film, usually near its tail. The **long axes of are parallel**

Answer 115

Pseudoelliptocytosis

Question 116

Other name for SOUTH-EAST ASIAN OVALOCYTOSIS

Answer 116

Melanesian elliptocytosis or stomatocytic elliptocytosis

Question 117

SAO is characterized by the presence of large oval red cells, many of which contain ____________

Answer 117

* 1 or 2 transverse ridges or a longitudinal slit * At least 20% ovalocytic red cells * Notable absence of clinical and laboratory evidence of hemolysis

Question 118

Sturctural abnormality in SAO

Answer 118

AE1(SLC4A1 gene ) ## Footnote Autosomal dominant

Question 119

Spiculated red cells are classified into 2 types:

Answer 119

A.Acanthocytes B. Echinocytes

Question 120

# What cell is being described: Contracted, dense cells with irregular projections from the red cell surface that vary in width and length

Answer 120

Acanthocytes

Question 121

# What cell is being described: Small, uniform projections spread evenly over the circumference of the red cell

Answer 121

Echinocytes

Question 122

Normal adults may have as many as____% of spiculated erythrocytes

Answer 122

3%

Question 123

Conditions where spiculated cells are seen

Answer 123

After transfusion with stored blood Ingestion of alcohol and certain drugs Exposure to ionizing radiation or certain venoms Hemodialysis Functional or actual splenectomy Severe liver disease Severe uremia Abetalipoproteinemia Inherited neurologic disorders Abnormalities of the Kell blood group Glycolytic enzyme defects Myelodysplasia Hypothyroidism Anorexia nervosa Vitamin E deficiency Premature infants Suppressed expression of Lua and Lub

Question 124

The anemia in patients with liver disease is often called

Answer 124

Spur-cell anemia

Question 125

Pathogenesis of spur cell anemia

Answer 125

Accumulation of free (nonesterified) cholesterol in the red cell membrane Remodeling of abnormally shaped red cells by the spleen

Question 126

Clinical features of spur cell anemia

Answer 126

Rapidly progressive hemolytic anemia with large numbers of acanthocytes on the blood film

Question 127

Spur-cell anemia is most common in patients with _______________,

Answer 127

Alcoholic liver disease

Question 128

# TRUE OR FALSE Splenectomy for spur cell anemia is a dangerous and potentially fatal procedure in these critically ill patients and is recommended

Answer 128

FALSE **Splenectomy is a dangerous and potentially fatal** procedure in these critically ill patients and is not recommended

Question 129

The prognosis for patients with alcoholic liver disease and more than ____% spur cells is very poor.

Answer 129

5%

Question 130

Only effective treatment option for spur cell anemia

Answer 130

A liver transplant combined with alcohol abstinence

Question 131

Common features are a **degeneration of neurons** and abnormal **acanthocytic** erythrocyte morphology

Answer 131

NEUROACANTHOCYTOSIS

Question 132

Types of neuroacanthocytosis syndromes:

Answer 132

(a) lipoprotein abnormalities **(abetalipoproteinemia and hypobetalipoproteinemia)** (b) neural degeneration of the basal ganglia **(chorea-acanthocytosis and McLeod syndrome)** (c) movement abnormalities **(Huntington disease-like 2 (HDL2) and pantothenate kinase-associated neurodegeneration)**

Question 133

Very rare **autosomal recessive** disorder characterized by **progressive ataxic** neurologic disease, **malabsorption of dietary fat and lipid-soluble vitamins (A, D, E, and K), retinal degradation, and acanthocytosis** Absent or extremely low low-density lipoprotein cholesterol, triglyceride, and apoB levels.

Answer 133

Abetalipoproteinemia / Bassen-Kornzweig syndrome

Question 134

The primary molecular defect in abetalipoproteinemia

Answer 134

Lack of the **microsomal triglyceride transfer protein (MTTP)** ## Footnote An essential cofactor for the assembly and secretion of lipoprotein particles that contain apolipoprotein B (apoB)

Question 135

The altered plasma lipid profile affects in Abetalipoproteinemia: phosphatidylcholine content is __________ with a corresponding ___________ in sphingomyelin.

Answer 135

Phosphatidylcholine: decreased Sphingomyelin: increased

Question 136

Primary cause of the **neuropathy** in Abetalipoproteinemia

Answer 136

Marked vitamin E deficiency ## Footnote Coagulopathy related to vitamin K deficiency may be observed.

Question 137

Therapy for Abetalipoproteinemia

Answer 137

Lifelong treatment with a **low-fat diet** and supplementation with **high oral doses of vitamins A, K, D, and E** ## Footnote Do not survive beyond the third decade of life.

Question 138

Rare **autosomal-recessive** movement disorder characterized by **atrophy of the basal ganglia** and progressive neurodegenerative disease with onset in adolescence or early adult life. The lipoproteins are normal. Patients are not anemic, and red cell survival is only slightly decreased.

Answer 138

Chorea-Acanthocytosis Syndrome

Question 139

Causative gene in Chorea-Acanthocytosis Syndrome

Answer 139

VPS13A (vacuolar protein sorting 13 homologue A) codes for **chorein**

Question 140

Expression of _________ is restricted to the **brain** and **hematopoietic tissues**, which corresponds to the main areas of pathology in chorea-acanthocytosis patients.

Answer 140

β-adducin

Question 141

Rare **X-linked** disorder of the **Kell** blood group system, whereby cells react poorly with Kell antisera, with cardiomyopathy

Answer 141

McLeod Syndrome

Question 142

Causative gene in McLeod Syndrome

Answer 142

XK protein

Question 143

Rare disorder caused by expanded **CGT/CAG trinucleotide repeats** in exon 2A of the Junctophilin-3 (JPH3) gene on chromosome 16q24.3 Features encompass involuntary movements, neuropsychiatric symptoms, and cognitive defect; autosomal dominant and Africa ancestry No anemia and acanthocytes (>30% Autosomal dominant

Answer 143

HDL2

Question 144

Characterized by progressive dystonia, and cognitive impairment in childhood, but no anemia Mutations in the PANK2 gene on chromosome 20p.13 coding for pantothenate kinase 2

Answer 144

Pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz syndrome)

Question 145

**Cup-shaped** red cells characterized by a central hemoglobin-free area

Answer 145

Stomatocytes

Question 146

Cells which are formed when there is **net loss of cations** dehydrates the cells

Answer 146

Xerocytes

Question 147

Causative genes in: Over-hydration syndromes: Dehydration syndromes:

Answer 147

Over-hydration syndromes: **RHAG, SLC4A1, and GLUT1** Dehydration syndromes: **PIEZO1 and KCNN4**

Question 148

**The most common form of the cation permeability defects.** Characterized by an **efflux of K+** May also exhibit **pseudohyperkalemia** and **perinatal edema** Strong tendency to **iron overload** regardless of transfusion history

Answer 148

Hereditary xerocytosis, also known as dehydrated hereditary stomatocytosis

Question 149

Defective gene in **Hereditary xerocytosis**

Answer 149

PIEZO1 KCNN4 (minority): Gardos channel, a calcium-activated K+ channel | Bigyan ng Piezo KC XerO

Question 150

Laboratory Features of Hereditary xerocytosis

Answer 150

* Mild to moderate compensated hemolytic anemia with an elevated reticulocyte count * K+ content is decreased and the Na+ content is increased, but the total monovalent cation content may be slightly reduced * MCHC is increased * Erythrocytes are resistant to osmotic lysis and the osmotic gradient ektacytometry curve is shifted to the left * Stomatocytes are not a prominent feature on blood films, but occasional target cells are seen * Hemoglobin is concentrated (“puddled”) in discrete areas on the cell periphery

Question 151

# TRUE OR FALSE Splenectomy does not significantly improve the anemia in Hereditary Xerocytosis

Answer 151

TRUE **Splenectomy does not significantly improve the anemia**, which suggests that xerocytes are detected and eliminated in other areas of the reticuloendothelial system. ## Footnote Markedly high risk of hypercoagulability and life-threatening **thrombotic** episodes after splenectomy, the procedure is **contraindicated**

Question 152

Very rare heterogeneous disorder characterized by a marked **passive sodium leak,** which increases the water content of the cell and causes **macrocytosis**

Answer 152

OVERHYDRATED HEREDITARY STOMATOCYTOSIS

Question 153

Pathogenesis of Hereditary hydrocytosis

Answer 153

Lack of **stomatin** ## Footnote Less often, very low levels of this 31-kDa integral membrane protein

Question 154

Gene mutations associated with Hereditary hydrocytosis

Answer 154

**NO gene mutations have been found**, which implies that the absence of the protein is a secondary phenomenon. **RhAG SLC4A1**

Question 155

Exhibits as mild cation leak that is markedly enhanced at **low temperatures** Associated with mild to moderate hemolytic anemia, and splenectomy appears to have **little or no effect**

Answer 155

Cryohydrocytosis

Question 156

Gene mutations associated with Cryohydrocytosis

Answer 156

GLUT1 gene | Exercise GLUTs u'll CRY

Question 157

Are very rare cases where the clinical phenotype and biochemical features of some patients with stomatocytes are intermediate between the extremes of **hereditary hydrocytosis and hereditary xerocytosis**.

Answer 157

Intermediate syndromes ## Footnote Mutations have been noted in the **PIEZO1** gene, but the defect is unknown in other instances.

Question 158

A rare condition that leads to accumulation of **cholesteryl esters** in many tissues, resulting in clinical findings of **large orange tonsils and hepatosplenomegaly**.

Answer 158

Familial deficiency of high-density lipoproteins

Question 159

Causes of scquired stomatocytosis

Answer 159

* Acute alcoholism * Vinca alkaloids * Long-distance runners immediately after a race ## Footnote The molecular basis of acquired stomato-cytosis is unknown.