PESG

1. What Is Paroxysmal Nocturnal Hemoglobinuria (PNH)?

Paroxysmal Nocturnal Hemoglobinuria (PNH), also referred to as Marchiafava-Micheli syndrome, is characterized by hemolytic anemia, bone marrow deficiency and thrombophilia. It is a non-malignant clonal disease of the hematopoietic stem cell PIG-A (phosphatidylinositol glycan class A), caused by the somatic mutation in the PIG-A (phosphatidylinositol glycan class A) gene, resulting in a deficiency in glycosylphosphatidylinositol-anchored proteins (GPI-AP). The absence of GPI-APs such as CD55 and CD59 makes erythrocytes vulnerable to complement mediated destruction, leading to intravascular hemolysis characteristic of PNH.

2. Is PNH Really Paroxysmal Nocturnal Hemoglobinuria?

PNH has initially been defined as sudden, irregular episodes of (paroxysmal) hemoglobinuria, especially at night, where patients pass dark colored urine early in the morning. However, the disease itself is not paroxysmal; the destructive, progressive effects of hemolysis are continuous. It is not nocturnal; as it causes complement activation of the acidic blood pH due to increased carbon dioxide pressure at night, leading to increased hemolysis during night time. However, hemolysis does not occur only at night. It is a process that continues 24 hours of a day. Furthermore, less than one thirds of patients have hemoglobinuria at the time of their diagnosis.

3. What are clinical symptoms and findings of PNH?

PNH patients may apply to different clinics with varying symptoms and findings. (Please see the "About PNH" section)
An internal diseases specialist and a hematologist may diagnose the disease based on laboratory abnormalities such as cytopenia, Coombs-negative hemolytic anemia, increased level of LDL, increased level of bilirubin, and low haptoglobin level. These findings may accompany an underlying bone marrow abnormality (such as AA), recurrent thrombosis, thrombosis in unusual locations, or gastrointestinal problems.
A nephrologist or a urologist may diagnose PNH, under the presence of accompanying laboratory findings following hemoglobinuria, renal failure or erectile dysfunction.
A gastroenterologist may diagnose PNH in patients with complaints such as abdominal pain or dysphagia accompanied by abnormal laboratory findings listed above, or following Budd-Chiari Syndrome, portal or venous thrombosis.

4. Which tests should be done for suspected PNH?

The flow cytometry test for identifying deficient GPI-AP represents the "golden standard" for diagnosing PNH. The test is done on a peripheral blood sample. The fluorescent aerolysin (FLAER) method is the most accurate method available today.

5. How can I reach guides on PNH tests?

Guidelines published by "The Clinical Cytometry Society" on identification and monitoring of PNH clones are listed below:
- Borowitz MJ et al. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom 2010; 78: 211-230.
- Sutherland DR et al. Practical guidelines for the high-sensitivity detection and monitoring of paroxysmal nocturnal hemoglobinuria clones by flow cytometry. Cytometry B Clin Cytom 2012; 82: 195-208.

6. Is there a correlation between the PNH clone and the increased risk of thrombosis?

Although previous studies indicate that a relationship exists between the PNH clone and the increased risk of thrombosis; recent studies have revealed that thrombotic events are independent from the granulocyte clone size. It has been concluded that while the frequency of development of thrombotic events in patients with a clone size of >50% is 20%; the frequency of thrombotic events in patients with a clone size of 20% is still high (16%).

7. What is the median survival time after PNH diagnosis?

Studies indicate that the median survival time for patients who do not undergo specific treatment, or who only receive supportive care (such as blood transfusion, androgen supplement treatment, low-dose steroids, etc.) is 10-15 years. However, this was obtained from studies that were carried out prior to the development of Eculizumab. Survival times were prolonged after the development of Eculizumab, a specific treatment method for PNH.

Although classic PNH and AA-PNH syndrome differ in terms of their clinical presentation or prognostic factors; complications (particularly thrombosis) are the same. While the cumulative thrombosis incidence 10 years after diagnosis is approximately 38% in classical PNH patients, it is at a level of 30% in AA-PNH patients. When we take into account the fact that the main parameter that accounts for mortality is thrombosis, it is possible to conclude that these two entities are in fact, no different.

8. Is there a chance of spontaneous remission in PNH?

A previously conducted study (Hillmen P et al. N Engl J Med 1995) indicates that spontaneous remission may be observed at a rate of 15%. Nevertheless, the publications in this subject are at case report level. The only explanation that can be made for this is that; like normal somatic cells, cells with PNH clone have a finite life cycle.

9. How can I reach guides on treatment of PNH?

Guidelines on diagnosis and management of PNH have been published by the "International PNH Interest Group" in 2005:

-Parker C et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005; 106: 3699-3709.

More recently, "The Australian Government's Department of Health and Ageing" and "The German Society for Haematology and Oncology" also published guidelines on treatment of PNH.

-Guidelines for the treatment of Paroxysmal Nocturnal Haemoglobinuria (PNH) through the Life Saving Drugs Program
-Paroxysmale nachtliche Hamoglobinurie (PNH)


<span style="\&quot;line-height:" 20.8px;\"="">http://www.ncbi.nlm.nih.gov/pubmed/27570707

 

10. Is allogeneic bone marrow transplant a treatment option for PNH?

Allogeneic hematopoietic stem cell transplantation is the only curative treatment for PNH. However, morbidity and mortality rates are high. Therefore, it is not a first-step treatment, but rather, an option that must be considered particularly for patients with bone marrow deficiency, young patients and patients with full-matched donors of relatives.

11. Is pregnancy a risk factor for PNH?

GPregnancy is a risk factor for PNH. According to a retrospective study, 25% of patients diagnosed with PNH are initially diagnosed during pregnancy. Hemolysis and bone marrow deficiency may worsen during pregnancy. Complications such as thrombotic events, infections, bleeding attacks and increased rate of miscarriage, fetal losses and premature birth may increase, along with an increase in both maternal mortality and infant mortality. However, it must be noted that the data obtained from these studies pertain to the period prior to the development of Eculizumab.

References

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3.Parker C et al. Blood 2005; 106: 3699-3709.
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10.Borowitz MJ et al. Cytometry B Clin Cytom 2010; 78B: 211-230.
11.Hillmen P et al. Am J Hematol 2010; 85: 553-559.
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13.Sutherland DR et al. Cytometry B Clin Cytom 2012; 82: 195-208.
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16.Hill A et al. Blood 2013; 121: 4985-4996.
17. Sahin F et al. Am J Blood Res. 2015 Jun 15;5(1):1-9.
18. Sahin F et al. Am J Blood Res. 2015 Jun 15;5(1):30-3.