Paroxysmal Nocturnal Paroxysmal Nocturnal Hemoglobinuria (PNH) Hemoglobinuria (PNH) PNH is an acquired chronic hemolytic PNH is an acquired chronic hemolytic anemia which arises from a somatic anemia which arises from a somatic mutation in a hematopoietic stem cell. mutation in a hematopoietic stem cell. Deficient in of the GPI-A complement Deficient in of the GPI-A complement regulatory proteins CD55 and CD59 regulatory proteins CD55 and CD59 renders the red cells highly renders the red cells highly susceptible to complement mediated susceptible to complement mediated lysis resulting in the characteristic lysis resulting in the characteristic hemolysis. hemolysis.
PNH is an acquired chronic hemolytic PNH is an acquired chronic hemolytic anemia which arises from a somatic anemia which arises from a somatic mutation in a hematopoietic stem cell. mutation in a hematopoietic stem cell.
Deficient in of the GPI-A complement Deficient in of the GPI-A complement regulatory proteins CD55 and CD59 regulatory proteins CD55 and CD59 renders the red cells highly susceptible renders the red cells highly susceptible to complement mediated lysis resulting to complement mediated lysis resulting in the characteristic hemolysis.in the characteristic hemolysis.
HistoryHistoryInvestigator Year ContributionInvestigator Year Contribution
Gull Gull 18661866 Described nocturnal and paroxysmal nature of Described nocturnal and paroxysmal nature of “intermittent haematinuria” in a young “intermittent haematinuria” in a young
tanner.tanner.Strubing Strubing 18821882 Distinguished PNH from paroxysmal cold Distinguished PNH from paroxysmal cold
haemoglobinuria and march haemoglobinuria and march haemoglobinuria. haemoglobinuria. Attributed the problem to Attributed the problem to the red cells. the red cells. van den Burgh van den Burgh 1911 1911 Red cells lysed in acidified serum. Red cells lysed in acidified serum. Suggested a role Suggested a role for complement.for complement.Enneking Enneking 19281928 Coined the name “Coined the name “paroxysmal paroxysmal nocturnal nocturnal haemoglobinuria”.haemoglobinuria”.Marchiafava Marchiafava 1928- 1928- Described perpetual hemosiderinemia in Described perpetual hemosiderinemia in absence of absence of and Micheli and Micheli 19311931 hemolysis. Their names became eponymous for hemolysis. Their names became eponymous for PNH PNH in Europe.in Europe.HamHam 19371937-- Identified the role of complement in Identified the role of complement in lysis of PNH red lysis of PNH red 19391939 cells. Developed the acidified cells. Developed the acidified serum test, also called serum test, also called the Ham test, which is still the Ham test, which is still used to diagnose PNH. used to diagnose PNH. Demonstrated that only a Demonstrated that only a portion of PNH red cells are portion of PNH red cells are abnormally abnormally sensitive to complement.sensitive to complement.DavitzDavitz 19861986 Suggests defect in membrane Suggests defect in membrane protein protein anchoring anchoring system responsiblesystem responsibleHall & RosseHall & Rosse 19961996 Flow cytometry for the diagnosis of PNHFlow cytometry for the diagnosis of PNH
thrombocytopeniathrombocytopenia - classical severe aplastic anemia- classical severe aplastic anemia
3. tendency to thrombosis3. tendency to thrombosis -venous thrombosis (40%) of patients-venous thrombosis (40%) of patients
Physical symptoms of PNH include:Physical symptoms of PNH include: Pallor - AnemiaPallor - Anemia Fever - Infection Fever - Infection Bleeding–skin ecchymoses in Bleeding–skin ecchymoses in
thrombocytopenia. thrombocytopenia. Specific symptoms involved with Specific symptoms involved with
vein thrombosis.vein thrombosis.
Minimal essential criteria required for Minimal essential criteria required for diagnosis and classificationdiagnosis and classification
Laboratory Evaluation of PNHLaboratory Evaluation of PNH
Acidified Serum Test (Ham Test 1939)Acidified Serum Test (Ham Test 1939)– Acidified serum activates alternative Acidified serum activates alternative
complement pathway resulting in lysis of complement pathway resulting in lysis of patient’s rbcspatient’s rbcs
– May be positive in congenitial dyserythropoietic May be positive in congenitial dyserythropoietic anemiaanemia
– Still in use todayStill in use today Sucrose Hemolysis Test (1970)Sucrose Hemolysis Test (1970)
– 10% sucrose provides low ionic strength which 10% sucrose provides low ionic strength which promotes complement binding resulting in lysis promotes complement binding resulting in lysis of patient’s rbcsof patient’s rbcs
– May be positive in megaloblastic anemia, May be positive in megaloblastic anemia, autoimmune hemolytic anemia, othersautoimmune hemolytic anemia, others
– Less specific than Ham testLess specific than Ham test
PNH Diagnosis by Flow Cytometry PNH Diagnosis by Flow Cytometry (1986)(1986)– Considered method of choice for Considered method of choice for
diagnosis of PNH (1996) diagnosis of PNH (1996) – Detects actual PNH clones lacking GPI Detects actual PNH clones lacking GPI
anchored proteinsanchored proteins– More sensitive and specific than Ham More sensitive and specific than Ham
and sucrose hemolysis testand sucrose hemolysis test
Laboratory Evaluation of PNHLaboratory Evaluation of PNH
Antigen expression is generally categorized into Antigen expression is generally categorized into three antigen density groupsthree antigen density groups– type I Normal Ag expressiontype I Normal Ag expression– type II Intermediate Ag expressiontype II Intermediate Ag expression– type III No Ag expressiontype III No Ag expression
Patient samples that demonstrate cell populations Patient samples that demonstrate cell populations with diminished or absent GPI-linked proteins with diminished or absent GPI-linked proteins (Type II or III cells) with multiple antibodies are (Type II or III cells) with multiple antibodies are
considered to be consistent with PNHconsidered to be consistent with PNH..
PNH Diagnosis by Flow CytometryPNH Diagnosis by Flow Cytometry
Who should e screened for PNHWho should e screened for PNH
Management anemia of PNHManagement anemia of PNH
Prior to initiating therapyPrior to initiating therapy
Effort should be made to determine how much of Effort should be made to determine how much of the anemia is a consequence of hemolysis and the anemia is a consequence of hemolysis and how much is due to impaired erythropoeisis.how much is due to impaired erythropoeisis.
Biochemical parameters of hemolysisi should Biochemical parameters of hemolysisi should be assessed.be assessed.
If the above assessment suggests that hemolysis If the above assessment suggests that hemolysis contribute significantly to anemia contribute significantly to anemia
Treat hemolysisTreat hemolysis
A. Treatment of hemolysis of PNH :A. Treatment of hemolysis of PNH :
1. Corticosteroids1. Corticosteroids
- for both chronic and acute - for both chronic and acute hemolytic exacerbationhemolytic exacerbation
brief pulse dose : reduced brief pulse dose : reduced severity and duration of crisisseverity and duration of crisis
2. androgens2. androgens
Given alone or in combo with steroids.Given alone or in combo with steroids.
Longterm use limited by complication of androgen Longterm use limited by complication of androgen therapy (liver toxicity, prostatic hypertrophy therapy (liver toxicity, prostatic hypertrophy and virilizing efect).and virilizing efect).
Use of Attenuated synthetic androgen for Use of Attenuated synthetic androgen for longterm is a reasonable option: longterm is a reasonable option:
Danazol starting dose 400 mg bid is Danazol starting dose 400 mg bid is recomended.recomended.
Dose : 600 mg iv every 7 day for the first Dose : 600 mg iv every 7 day for the first 4 weeks4 weeks
followed by 900 mg for the 5 dose followed by 900 mg for the 5 dose 7 day later7 day later
than 900 mg avery 14 days than 900 mg avery 14 days thereafter.thereafter.
B. Iron replacementB. Iron replacement
- Px with PNH frequently become iron deficient Px with PNH frequently become iron deficient
as a result of Hb-uria and hemosiderinuriaas a result of Hb-uria and hemosiderinuria..
- Compared to parenteral replacement, oral Compared to parenteral replacement, oral administration of iron may be accompanied administration of iron may be accompanied by less exacerbation but the loss so great by less exacerbation but the loss so great that repletion cannot be achieved through that repletion cannot be achieved through this mechanism.this mechanism.
- Parenteral repletion is generally safe. Parenteral repletion is generally safe.
c. transfusionc. transfusion
Ameliorate hemolysis by supressing Ameliorate hemolysis by supressing erythropoeisiserythropoeisis
to prevent transfusion Rx to prevent transfusion Rx Hemofiltrasion is Hemofiltrasion is recommendedrecommended
When anemia is primarily a consequence of When anemia is primarily a consequence of marrow failure rather than hemolysis, iron marrow failure rather than hemolysis, iron overload remains a concern due to chronic overload remains a concern due to chronic transfusion. transfusion.
D. Folate D. Folate
Suplemental folate 5 mg/day is recommended Suplemental folate 5 mg/day is recommended to compensate for increase utilization to compensate for increase utilization associated w/associated w/
Heightened erythropoeisis that is consequence Heightened erythropoeisis that is consequence of hemolysis.of hemolysis.
Recurrent life threatening thrombosis Recurrent life threatening thrombosis considered BMTconsidered BMT
PNH and pregnancyPNH and pregnancy
- Pregnancy worsen px w/ PNHPregnancy worsen px w/ PNH- All cause mortality 20.8%All cause mortality 20.8%- Thromboembolism 10%Thromboembolism 10%
prognosisprognosis
25% of PNH patients survive >25 years - 25% of PNH patients survive >25 years - one half of these go on to spontaneous one half of these go on to spontaneous remissionremission
Remission patientsRemission patients– hematological values revert to normalhematological values revert to normal– no PHN rbcs or granulocytes detectedno PHN rbcs or granulocytes detected– PNH lymphocytes - still detected but no clinical PNH lymphocytes - still detected but no clinical
consequenceconsequence Higher incidence of acute leukemia (6%)Higher incidence of acute leukemia (6%)
– ““preleukemic condition” most likely bone preleukemic condition” most likely bone marrow failure not PNH marrow failure not PNH
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