41 Paroxysmal Nocturnal Hemoglobinuria Flashcards
PNH arises from clonal expansion of one or several hematopoietic HS/PCs that have acquired a somatic mutation of the _______________ gene
X-chromosome gene PIGA (phosphatidylinositol gly class A)
Located on Xp22.1
TRUE OR FALSE
Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder of hematopoietic stem/progenitor cells (HS/PCs)
TRUE
Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder of hematopoietic stem/progenitor cells (HS/PCs)
The clinical manifestations of PNH are
Hemolytic anemia, thrombophilia, and marrow failure
Only manifestation that is unequivocally a consequence of somatic mutation of PIGA
Hemolytic anemia
TRUE OR FALSE
PNH is a clonal disease and is a malignant neoplasm
FALSE
PNH is a clonal disease, but not a malignant neoplasm
The major cause of morbidity and mortality in PNH
Thrombosis
The peak incidence of PNH
Third and fourth decades of life
like with AA
The hallmark clinical manifestation of PNH
Chronic intravascular hemolysis
The chronic intravascular hemolysis that is the hallmark clinical manifestation of PNH is mediated by the
Alternative pathway of complement (APC)
Normal human erythrocytes are protected against APC-mediated cytolysis, primarily by
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
The pathophysiologic basis of the direct antiglobulin test–negative, intravascular hemolysis in PNH
Deficiency of CD55 and CD59 on the erythrocytes
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:
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
The most common phenotype of PNH
- Type I and type III cells (most common; high grade hemolysis)
- Type I, type II, and type III (the second most common phenotype; minimal hemolysis)
- Type I and type II cells (the least common phenotype; minimal hemolysis)
Nocturnal hemoglobinuria being a presenting symptom in PNH occurs in approximately_____of patients
25%
TRUE OR FALSE
Venous thrombosis is as common as arterial thrombosis
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.
Recommendation for Screening Patients for Paroxysmal Nocturnal Hemoglobinuria
- History of episodic hemoglobinuria
- Evidence of nonspherocytic, Coombs’-negative (direct antiglobulin test) intravascular hemolysis (must have high serum LDH)
- Patients with aplastic anemia (screen at diagnosis and once yearly even in the absence of intravascular hemolysis)
- Patients with refractory anemia (RA) or refractory cytopenias with multilineage dysplasia (RCMD) variants of myelodysplastic syndrome (MDS)
- Patients with venous thrombosis involving unusual sites (usually have evidence of intravascular hemolysis):
Budd-Chiari syndrome
Other intraabdominal sites
Cerebral veins
Dermal veins
The clinical manifestations of PNH depend largely on
Size of the PIGA mutant clone
The extent of the associated marrow failure also contributes to disease manifestations.
The most commonly associated marrow failure syndromes with PNH
Aplastic anemia and refractory anemia/MDS
TRUE OR FALSE
Analysis of PMNs is more informative than analysis of RBCs because of selective destruction of GPI-AP–deficient red blood cells.
TRUE
Analysis of PMNs is more informative than analysis of RBCs because of selective destruction of GPI-AP–deficient red blood cells.
GPI-AP–deficient cells is smaller than 1% of the total
Subclinical PNH
Patients with PNH-sc have neither clinical nor biochemical evidence of hemolysis
Classification of PNH that may benefit from Eculizumab
- Classic PNH
- PNH in the setting of another marrow failure syndrome (Dependent on the size of the PNH clone)
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
Serum lactate dehydrogenase (LDH)
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.
50% AA
15% MDS
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.
Aerolysin
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.
FLAER
Tests that have largely been abandoned as diagnostic assays because they are both less sensitive and less quantitative than flow cytometry.
Acidified serum lysis test (Ham test) and the sucrose lysis test (sugar water test)
TRUE OR FALSE
Patients with classic PNH are often iron deficient from chronic iron loss in the form of hemoglobinuria and hemosiderinuria
TRUE
Patients with classic PNH are often iron deficient from chronic iron loss in the form of hemoglobinuria and hemosiderinuria
TRUE OR FALSE
Nonrandom cytogenetic abnormalities are common in PNH.
FALSE
Nonrandom cytogenetic abnormalities are rare in PNH.
Used to distinguish classic PNH from PNH in the setting of another marrow abnormality.
Marrow aspirate and biopsy
PNH clone size is determined by the percentage of
GPI-AP–deficient neutrophils
NOT RBCs
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 ________
25% neutrophil
3% to 5% RBC
Among patients who present with clinical PNH in the setting of marrow failure, treatment for complications of PNH (eculizumab for hemolysis or anticoagulation for thrombosis) is required in approximately _____ % of cases.
50%
There is no evidence that treatment with immunosuppressive therapy influences clonal expansion either positively or negatively.
Patients with RA with a population of PNH cells (RA-PNH+) had a distinct clinical profile characterized by the following features:
- (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
TRUE OR FALSE
A relatively good response to immunosuppressive therapy for patients with PNH with MDS and aplastic anemia
TRUE
A relatively good response to immunosuppressive therapy for patients with PNH with MDS and aplastic anemia
A humanized monoclonal antibody that binds to complement C5, preventing its activation to C5b and thereby inhibiting MAC formation
Eculizumab
Mild to moderate anemia and reticulocytosis usually persist after treatment with Eculizumab because of:
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
Dose of Eculizumab
Intravenous infusion on a biweekly schedule after an initial loading period of five weekly treatments
Giving Eculizumab makes patient at risk for which infections
Neisseria species (patients with congenital deficiency of complement C5)
Meningococcal species
All patients must be inoculated with a meningococcal vaccine two weeks before starting therapy, but the vaccine is not 100% effective.
Breakthrough hemolysis with Eculizumab use can be diagnosed by monitoring the
Patients treated with eculizumab may become symptomatic (fatigue, lethargy, worsening anemia, hemoglobinuria) near the end of the 14-day treatment cycles.
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.
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
Ravulizumab
Noninferior to eculizumab
Cheaper
The main value of glucocorticoids in treatment of PNH
Attenuating acute hemolytic exacerbations
Other than eculizumab/ravulizumab, there is no specific treatment for PNH, and for patients who are not being treated with eculizumab/ ravulizumab, treatment is largely supportive.
Used successfully to treat the anemia of PNH
Androgen therapy
Danazol 400 mg twice a day
SE: liver toxicity, prostatic hypertrophy, and virilizing effects
TRUE OR FALSE
Hemofiltration is recommended to prevent transfusion reaction arising from the interaction between donor leukocytes and recipient antibodies
TRUE
Hemofiltration is recommended to prevent transfusion reaction arising from the interaction between donor leukocytes and recipient antibodies
TRUE OR FALSE (IRON REPLACEMENT)
Replacement is often associated with exacerbation of hemolysis, regardless of the route of administration.
TRUE
Replacement is often associated with exacerbation of hemolysis, regardless of the route of administration.
Compared with parenteral replacement, oral administration of iron may be accompanied by less severe hemolytic exacerbations
Recommended dose of folate to compensate for increased utilization associated with heightened erythropoiesis that is a consequence of ongoing hemolysis
Folate (1 mg/day)
The only curative therapy for PNH
HSCT
Indications for Transplantation
- Marrow failure
- Major complications of PNH
- Refractory, transfusion-dependent hemolytic anemia
- Recurrent, life-threatening thromboembolic complications
Overall survival for unselected PNH patients who undergo transplantation using a HLA-matched sibling donor is in the range of _______.
50% to 60%
Patients with more than ________% GPI-AP–deficient neutrophils be offered prophylactic anticoagulation.
More than 50% to 60%
Anticoagulant recommended for patients with PNH who require chronic anticoagulation either for treatment of a thromboembolic event or for prophylaxis.
Warfarin
There are no evidence-based data to guide the use of low-molecular-weight heparin or direct oral anticoagulants
Arterial or venous
Thromboembolic events in patients with PNH usually involve the ________ system
Venous system
Acute thrombotic events require anticoagulation with
Heparin
Patients with PNH who experience a thromboembolic event should be anticoagulated__________ (duration)
Indefinitely
TRUE OR FALSE
For patients being treated with eculizumab/ravulizumab who have no prior history of thromboembolic complications, prophylactic anticoagulation is necessary.
FALSE
For patients being treated with eculizumab/ravulizumab who have no prior history of thromboembolic complications, prophylactic anticoagulation may not be necessary.
Eculizumab reduces the risk of thromboembolic complications.
TRUE OR FALSE
Prophylaxis in pregnancy is recommended among patients with PNH
TRUE
Prophylaxis in pregnancy is recommended among patients with PNH
Anticoagulation with heparin should begin immediately once pregnancy is confirmed
Commonly involved sites of thrombosis during pregnancy and the postpartum period:
Cerebral and hepatic veins
Similar to nonpregnant patients with PNH
TRUE OR FALSE
Gross hemoglobinuria as a presenting symptom may be more common in young patients with PNH.
FALSE
Gross hemoglobinuria as a presenting symptom may be less common in young patients with PNH.
