41 Paroxysmal Nocturnal Hemoglobinuria

Question 1

PNH arises from clonal expansion of one or several hematopoietic HS/PCs that have acquired a somatic mutation of the _______________ gene

Answer 1

X-chromosome gene PIGA (phosphatidylinositol gly class A)

Question 2

TRUE OR FALSE

Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder of hematopoietic stem/progenitor cells (HS/PCs)

Answer 2

TRUE

Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder of hematopoietic stem/progenitor cells (HS/PCs)

Question 3

The clinical manifestations of PNH are

Answer 3

Hemolytic anemia, thrombophilia, and marrow failure

Question 4

Only manifestation that is unequivocally a consequence of somatic mutation of PIGA

Answer 4

Hemolytic anemia

Question 5

TRUE OR FALSE

PNH is a clonal disease and is a malignant neoplasm

Answer 5

FALSE

PNH is a clonal disease, but not a malignant neoplasm

Question 6

The major cause of morbidity and mortality in PNH

Answer 6

Thrombosis

Question 7

The peak incidence of PNH

Answer 7

Third and fourth decades of life

Question 8

The hallmark clinical manifestation of PNH

Answer 8

Chronic intravascular hemolysis

Question 9

The chronic intravascular hemolysis that is the hallmark clinical manifestation of PNH is mediated by the

Answer 9

Alternative pathway of complement (APC)

Question 10

Normal human erythrocytes are protected against APC-mediated cytolysis, primarily by

Answer 10

Decay-accelerating factor (CD55) : regulates the formation and stability of the C3 and C5 convertases

Membrane inhibitor of reactive lysis (CD59): blocks the formation of the MAC

Question 11

The pathophysiologic basis of the direct antiglobulin test–negative, intravascular hemolysis in PNH

Answer 11

Deficiency of CD55 and CD59 on the erythrocytes

Question 12

Another remarkable feature of PNH is phenotypic mosaicism (based on PIGA genotype) that determines the degree of GPI-AP deficiency.

PNH III :
PNH II:
PNH I:

Answer 12

PNH III : completely deficient in GPI-APs
PNH II: partially (~90%) deficient
PNH I: GPI-APs at normal density

**PNH II cells are relatively resistant to spontaneous hemolysis, and patients with a high percentage of type II cells have a relatively benign clinical course with respect to hemolysis

Question 13

The most common phenotype of PNH

Answer 13

Type I and type III cells

Type I, type II, and type III (the second most common phenotype)

Type I and type II cells (the least common phenotype).

Question 14

Nocturnal hemoglobinuria being a presenting symptom in PNH occurs in approximately_____of patients

Answer 14

25%

Question 15

TRUE OR FALSE

Venous thrombosis is as common as arterial thrombosis

Answer 15

FALSE

Venous thrombosis, often occurring at unusual sites (Budd-Chiari syndrome, mesenteric, portal vein, dermal or cerebral veins), may complicate PNH. Arterial thrombosis is less common.

Question 16

The clinical manifestations of PNH depend largely on

Answer 16

Size of the PIGA mutant clone

Question 17

The most commonly associated marrow failure syndromes with PNH

Answer 17

Aplastic anemia and refractory anemia/MDS

Question 18

TRUE OR FALSE

Analysis of PMNs is more informative than analysis of RBCs because of selective destruction of GPI-AP–deficient red blood cells.

Answer 18

TRUE

Analysis of PMNs is more informative than analysis of RBCs because of selective destruction of GPI-AP–deficient red blood cells.

Question 19

Classification of PNH that may benefit from Eculizumab

Answer 19

Classic

PNH in the setting of another marrow failure
syndrome
**Dependent on the size of the PNH clone

Question 20

Serves as an important surrogate marker for estimating and following the rate of intravascular hemolysis

Concentration is always abnormally high in patients with clinically significant hemolysis

Answer 20

Serum lactate dehydrogenase (LDH)

Question 21

By using high-sensitivity flow cytometry, approximately____% of patients with aplastic anemia and ____% of patients with low-risk MDS have been found to have a detectable population of GPI-AP–deficient erythrocytes and granulocytes.

Answer 21

50% AA

15% MDS

Question 22

The pore-forming bacterial protein, ________, secreted from Aeromonas hydrophila, binds to the GPI moiety of GPI-APs and, upon oligomerization, forms transmembrane channels that induce osmotic cytolysis.

Answer 22

Aerolysin

Question 23

A genetically modified form of aerolysin has been developed that does not induce cytolysis

Can be used in flow cytometric assays to detect GPI-AP–deficient cells.

Answer 23

FLAER

Question 24

Tests that have largely been abandoned as diagnostic assays because they are both less sensitive and less quantitative than flow cytometry.

Answer 24

Acidified serum lysis test (Ham test) and the sucrose lysis test (sugar water test)

Question 25

TRUE OR FALSE

Patients with classic PNH are often iron deficient from chronic iron loss in the form of hemoglobinuria and hemosiderinuria

Answer 25

TRUE

Patients with classic PNH are often iron deficient from chronic iron loss in the form of hemoglobinuria and hemosiderinuria

Question 26

TRUE OR FALSE

Nonrandom cytogenetic abnormalities are common in PNH.

Answer 26

FALSE

Nonrandom cytogenetic abnormalities are rare in PNH.

Question 27

Used to distinguish classic PNH from PNH in the setting of another marrow abnormality.

Answer 27

Marrow aspirate and biopsy

Question 28

PNH clone size is determined by the percentage of

Answer 28

GPI-AP–deficient neutrophils

Question 29

The threshold that separates subclinical PNH from clinical PNH is reached when the neutrophil clone size is in the range of ______ with a corresponding GPI-AP–deficient erythrocyte population of __________

Answer 29

25%

3% to 5%

Question 30

Patients with RA with a population of PNH cells (RA-PNH+) had a distinct clinical profile characterized by the following features:

Answer 30

(1) less pronounced morphologic abnormalities of blood cells,
(2) more severe thrombocytopenia,
(3) lower rates of karyotypic abnormalities,
(4) higher incidence of human leukocyte antigen (HLA)-DR15,
(5) lower rate of progression to acute leukemia, and
(6) higher probability of response to cyclosporine therapy

Question 31

TRUE OR FALSE

A relatively good response to immunosuppressive therapy for patients with PNH with MDS and aplastic anemia

Answer 31

TRUE

A relatively good response to immunosuppressive therapy for patients with PNH with MDS and aplastic anemia

Question 32

A humanized monoclonal antibody that binds to complement C5, preventing its activation to C5b and thereby inhibiting MAC formation

Answer 32

Eculizumab

Question 33

Mild to moderate anemia and reticulocytosis usually persist after treatment with Eculizumab because of:

Answer 33

Ongoing extravascular hemolysis mediated by opsonization of PNH erythrocytes by activated complement C3, because eculizumab does not block the activity of the APC C3 convertase

Question 34

Dose of Eculizumab

Answer 34

Intravenous infusion on a biweekly schedule after an initial loading period of five weekly treatments

Question 35

Giving Eculizumab makes patient at risk for which infections

Answer 35

Neisseria species (patients with congenital deficiency of complement C5)

Meningococcal species

Question 36

Breakthrough hemolysis with Eculizumab use can be diagnosed by monitoring the

Answer 36

CH50 or the concentration of free eculizumab

Detectable levels of CH50 (≥10% of normal) and concentrations of eculizumab lower than 50 mcg/mL suggest suboptimal dosing of eculizumab.

This issue can be addressed by increasing the dose of eculizumab from 900 mg every 2 weeks to 1200 mg every 2 weeks or by shorting the dosing interval from 14 days to 12 days.

Question 37

A humanized, monoclonal antibody that binds to complement C5

Engineered to take advantage of immunoglobulin recycling by the neonatal Fc receptor hence an extended the half-life allowing for dosing every 8 weeks

Noninferior to eculizumab

Answer 37

Ravulizumab

Question 38

The main value of glucocorticoids in treatment of PNH

Answer 38

Attenuating acute hemolytic exacerbations

Question 39

Used successfully to treat the anemia of PNH

Answer 39

Androgen therapy

Danazol 400 mg twice a day

Question 40

The only curative therapy for PNH

Answer 40

HSCT

Question 41

Indications for Transplantation

Answer 41

• Marrow failure
• Major complications of PNH
• Refractory, transfusion-dependent hemolytic anemia
• Recurrent, life-threatening thromboembolic complications

Question 42

Overall survival for unselected PNH patients who undergo transplantation using a HLA-matched sibling donor is in the range of _______.

Answer 42

50% to 60%

Question 43

Patients with more than ________% GPI-AP–deficient neutrophils be offered prophylactic anticoagulation.

Answer 43

More than 50% to 60%

Question 44

Anticoagulant recommended for patients with PNH who require chronic anticoagulation either for treatment of a thromboembolic event or for prophylaxis.

Answer 44

Warfarin

There are no evidence-based data to guide the use of low-molecular-weight heparin or direct oral anticoagulants

Question 45

Thromboembolic events in patients with PNH usually involve the ________ system

Answer 45

Venous system

Question 46

Acute thrombotic events require anticoagulation with

Answer 46

Heparin

Question 47

Patients with PNH who experience a thromboembolic event should be anticoagulated__________ (duration)

Answer 47

Indefinitely

Question 48

TRUE OR FALSE

For patients being treated with eculizumab/ravulizumab who have no prior history of thromboembolic complications, prophylactic anticoagulation is necessary.

Answer 48

FALSE

For patients being treated with eculizumab/ravulizumab who have no prior history of thromboembolic complications, prophylactic anticoagulation may not be necessary.

Question 49

TRUE OR FALSE

Prophylaxis in pregnancy is recommended among patients with PNH

Answer 49

TRUE

Prophylaxis in pregnancy is recommended among patients with PNH

Question 50

Commonly involved sites of thrombosis during pregnancy and the postpartum period:

Answer 50

Cerebral and hepatic veins