Paroxysmal Nocturnal Hemoglobinuria (PNH)

PNH is an acquired chronic hemolytic anemia which arises from a somatic mutation in a hematopoietic stem cell. Deficient in of the GPI-A complement regulatory proteins CD55 and CD59 renders the red cells highly susceptible to complement mediated lysis resulting in the characteristic hemolysis.

History
Investigator
Gull

Year
1866

Contribution

Described nocturnal and paroxysmal nature of intermittent haematinuria in a young tanner. Strubing 1882 Distinguished PNH from paroxysmal cold haemoglobinuria and march haemoglobinuria. Attributed the problem to the red cells. van den Burgh 1911 Red cells lysed in acidified serum. Suggested a role for complement. Enneking 1928 Coined the name paroxysmal nocturnal haemoglobinuria. Marchiafava 1928- Described perpetual hemosiderinemia in absence of and Micheli 1931 hemolysis. Their names became eponymous for PNH in Europe. Ham 1937 - Identified the role of complement in lysis of PNH red 1939 cells. Developed the acidified serum test, also called the Ham test, which is still used to diagnose PNH. Demonstrated that only a portion of PNH red cells are abnormally sensitive to complement. Davitz 1986 Suggests defect in membrane protein anchoring system responsible Hall & Rosse 1996 Flow cytometry for the diagnosis of PNH

Epidemiology

Rare disease frequency unknown thought to be on the same order as aplastic anemia (2-6 per million)

Median age at diagnosis

~ 35 yrs PNH reported at extremes of age

Female:Male ratio = 1.2:1.0 No increased risk of PNH in patient relatives Median Survival after diagnosis ~ 10-15 yrs

Classification

Classical PNH PNH-in the setting of another specified bone marow disorder (eg PNH/aplastic anemia or PNH/refractory anemiaMDS) PNH subclinical (PNHsc)in the setting of another specified bone marow disorder (eg PNHsc/aplastic anemia)

Major symptom
1. Hemolysis
Recurrent attacks of intravascular hemolysis usually associated :
hemoglobinuria abdominal pain dysphagia

2. Cytopenia - isolated subclinical thrombocytopenia - classical severe aplastic anemia

3. tendency to thrombosis -venous thrombosis (40%) of patients

Physical symptoms of PNH include:

Pallor - Anemia Fever - Infection Bleedingskin ecchymoses in thrombocytopenia. Specific symptoms involved with vein thrombosis.

Minimal essential criteria required for diagnosis and classification

Laboratory Evaluation of PNH

Acidified Serum Test (Ham Test 1939)

Acidified serum activates alternative complement pathway resulting in lysis of patients rbcs May be positive in congenitial dyserythropoietic anemia Still in use today

Sucrose Hemolysis Test (1970)

10% sucrose provides low ionic strength which promotes complement binding resulting in lysis of patients rbcs May be positive in megaloblastic anemia, autoimmune hemolytic anemia, others Less specific than Ham test

Laboratory Evaluation of PNH

PNH Diagnosis by Flow Cytometry (1986) Considered method of choice for diagnosis of PNH (1996) Detects actual PNH clones lacking GPI anchored proteins More sensitive and specific than Ham and sucrose hemolysis test

PNH Diagnosis by Flow Cytometry

Antigen expression is generally categorized into three antigen density groups type I Normal Ag expression type II Intermediate Ag expression type III No Ag expression Patient samples that demonstrate cell populations with diminished or absent GPI-linked proteins (Type II or III cells) with multiple antibodies are considered to be consistent with PNH.

Who should e screened for PNH

Management anemia of PNH

Prior to initiating therapy Effort should be made to determine how much of the anemia is a consequence of hemolysis and how much is due to impaired erythropoeisis. Biochemical parameters of hemolysisi should be assessed. If the above assessment suggests that hemolysis contribute significantly to anemia Treat hemolysis

A. Treatment of hemolysis of PNH :

1. Corticosteroids - for both chronic and acute hemolytic exacerbation - prednison 0.25-1 mg/kg/d acute hemolytic exacerbation : brief pulse dose : reduced severity and duration of crisis

2. androgens Given alone or in combo with steroids. Longterm use limited by complication of androgen therapy (liver toxicity, prostatic hypertrophy and virilizing efect). Use of Attenuated synthetic androgen for longterm is a reasonable option: Danazol starting dose 400 mg bid is recomended. chronic hemolysis : low dose 200 400 mg/day. Monitoring liver function.

3. Complement inhibitor : Eculizumab

Humanized monoclonal antibody againts complement C5. Inhibit terminal complement activation Is an effective therapy for PNH (cinicaltrial.gov NCT 00122330).

Dose : 600 mg iv every 7 day for the first 4 weeks followed by 900 mg for the 5 dose 7 day later than 900 mg avery 14 days thereafter.

B. Iron replacement
-

Px with PNH frequently become iron deficient as a result of Hb-uria and hemosiderinuria. Compared to parenteral replacement, oral administration of iron may be accompanied by less exacerbation but the loss so great that repletion cannot be achieved through this mechanism. Parenteral repletion is generally safe.

c. transfusion

Ameliorate hemolysis by supressing erythropoeisis to prevent transfusion Rx Hemofiltrasion is recommended When anemia is primarily a consequence of marrow failure rather than hemolysis, iron overload remains a concern due to chronic transfusion.

D. Folate Suplemental folate 5 mg/day is recommended to compensate for increase utilization associated w/ Heightened erythropoeisis that is consequence of hemolysis.

Management Of thrombosis
Prophylaxis : - PNH px w/ > 50% GPI-AP deficient granulocyte - Px w/ PNH who experienced thromboembolic events warfarin : target INR 2.0-3.0 is recommended for chronic therapy Acute thrombotic events : anticoagulation w/ heparin Recurrent life threatening thrombosis considered BMT

PNH and pregnancy

-

Pregnancy worsen px w/ PNH All cause mortality 20.8% Thromboembolism 10%

prognosis

Long term

25% of PNH patients survive >25 years - one half of these go on to spontaneous remission Remission patients
hematological values revert to normal no PHN rbcs or granulocytes detected PNH lymphocytes - still detected but no clinical consequence

Higher incidence of acute leukemia (6%)

preleukemic condition most likely bone marrow failure not PNH