What are the other Names for this Condition? (Also known as/Synonyms)

• Marchiafava-Micheli Syndrome
• Paroxysmal Hemoglobinuria
• PNH (Paroxysmal Nocturnal Hemoglobinuria)

What is Paroxysmal Nocturnal Hemoglobinuria? (Definition/Background Information)

• Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare disorder of the blood, whereby there is defective production and premature destruction of red blood cells (RBCs). This disorder is characterized by the presence of red blood in the urine
• The term ‘paroxysmal’ indicates that the disorder is not continuous but interrupted, and the breakdown of blood cells occurred only at night (nocturnal). However, hemolysis occurs during daytime as well, although ‘hemoglobinuria’ (high levels of hemoglobin in urine) may be occurring in intermittent episodes
• Hemolysis affects the way oxygen gets delivered throughout the body. Additionally, the white blood cells and platelets are also affected in this condition
• Paroxysmal Nocturnal Hemoglobinuria is an acquired hematopoietic stem cell disorder; it is not inherited. It is a serious disorder, and because of the defects in the blood cells, it could potentially affect every organ in the body
• PNH generally affects young adults between 35-40 years of age. About 30% of PNH cases arise from aplastic anemia - either in those with aplastic anemia or after being treated for the condition
• Individuals with aplastic anemia and those having undergone immunosuppressant therapy for the same, are the only risk factors reported for acquiring Paroxysmal Nocturnal Hemoglobinuria
• The chief cause of Paroxysmal Nocturnal Hemoglobinuria is a mutation of a gene called PIG-A, in the blood-generating bone marrow stem cells of an individual. This gene is responsible for the synthesis of an anchor molecule known as GPI. When GPI anchor molecules are present on red blood cells, they interact with a component of the immune system known as ‘complement’. So, when GPI anchor is defective or missing, ‘complement’ is unable to bind to the cell surface, leading to destruction of the red blood cells
• The defective bone marrow also leads to abnormalities in other blood types, such as white blood cells and blood platelets. The white blood cells are involved in immune function, and hence, there are reports of the abnormal white blood cells attacking the red blood cells (autoimmune process) in PNH as well
• Since different types of blood cells have unique functions, PNH could affect individuals in many different ways, with a wide spectrum of symptoms. The number and type of abnormal blood cells also dictate the kind and severity of symptoms
• Symptoms of Paroxysmal Nocturnal Hemoglobinuria include shortness of breath, being prone to infections, anemic appearance, bleeding issues, abdominal pain, severe headaches, and blood in the urine
• There are a host of complications that could arise from PNH including lethargy, renal failure, clotting issues, heart attack, stroke, leukemia, aplastic anemia, and reduced quality of life
• The diagnosis of Paroxysmal Nocturnal Hemoglobinuria is a challenge, owing to the wide spectrum of symptoms. It is not unusual to obtain a proper diagnosis several months after appearance of symptoms. When PNH is suspected, several tests may be ordered, such as sucrose hemolysis test, ham test, flow cytometry test (to measure certain protein levels), and other tests to confirm or rule out the disorder
• Treatment options for PNH depend on the type and severity of symptoms. In some patients, the symptoms could be mild, requiring minimal treatment. In others, aggressive treatment to reduce red blood cell denaturation or blood clots may be required. In severe cases, blood transfusions or bone marrow transplant from a suitable donor could become necessitated
• The most important thing to consider is that Paroxysmal Nocturnal Hemoglobinuria could be managed with treatment. In fact, treatment is vital to evading some serious consequences of the disorder
• Paroxysmal Nocturnal Hemoglobinuria is a progressive condition and therefore, the median survival time after diagnosis depends on the severity of symptoms and successful management of the symptoms 

Who gets Paroxysmal Nocturnal Hemoglobinuria? (Age and Sex Distribution)

• Paroxysmal Nocturnal Hemoglobinuria is a rare disorder, affecting 1-2 individuals per million among the general population
• Individuals in their 30s are reported to be more prone to PNH, although it is known to occur in other age groups as well
• Both male and female genders are at equal risk
• All races and ethnicities are susceptible to PNH
• However, populations that are more prone to aplastic anemia (such as from South East Asia) may be more susceptible to PNH

What are the Risk Factors for Paroxysmal Nocturnal Hemoglobinuria? (Predisposing Factors)

The following are some reported risk factors for developing Paroxysmal Nocturnal Hemoglobinuria:

• Individuals with certain health conditions such as aplastic anemia
• Having undergone treatment for aplastic anemia with immunosuppressive therapy

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Paroxysmal Nocturnal Hemoglobinuria? (Etiology)

Paroxysmal Nocturnal Hemoglobinuria develops as a result of a mutation in the PIG-A gene.

• The defective PIG-A gene in the bone marrow stem cells can cause reduced numbers of all blood cell types
• The defective PIG-A leads to the reduced synthesis of GPI molecule, leading to increased breaking of red blood cells. The GPI molecule needs to interact with ‘complement’ (a component of the immune system) to protect red blood cells from breaking-down
• Abnormal white blood cells could lead to an autoimmune response, by which they attack red blood cells, resulting in the disintegration of the RBCs

What are the Signs and Symptoms of Paroxysmal Nocturnal Hemoglobinuria?

Since Paroxysmal Nocturnal Hemoglobinuria could potentially affect all types of blood cells in an individual, the symptoms will depend upon the type of blood cell affected and the extent of damage. The following are some known symptoms of PNH:

• Red blood in the urine (dark, tea-colored urine in the morning, which may be clear as the day progresses)
• Bleeding gums, easy bruising
• Back pain
• Severe headache and difficulties with thinking (owing to blood clots in the cerebral veins)
• Feeling very weak
• Severe abdominal pain (because of blood clots affecting the stomach and bowels)
• Jaundice (as a result of blood clots affecting the liver)
• Repeated infections
• Shortness of breath
• Menorrhagia (excessive bleeding during menses in women)
• Weight loss

How is Paroxysmal Nocturnal Hemoglobinuria Diagnosed?

When a physician suspects Paroxysmal Nocturnal Hemoglobinuria, he/she might order several tests to confirm or rule out the condition. Some of the tests ordered could include:

• Blood test to get counts of red blood cells, white blood cells, and platelets
• Analysis of urine
• Acid hemolysin (ham’s) test
• Sucrose hemolysis test
• Flow cytometry to measure the level of certain proteins
• Test to ascertain serum hemoglobin

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Paroxysmal Nocturnal Hemoglobinuria?

If left untreated, following are some of the complications that could arise as a result of Paroxysmal Nocturnal Hemoglobinuria:

• Anemia
• Acute myeloid leukemia
• Excessive bleeding from small wounds
• Budd-Chiari syndrome (from blood clots affecting the liver)
• Thrombosis (formation of blood clots)
• Fatigue, to such an extent that it becomes very difficult to perform even ordinary, everyday activities
• Aplastic anemia
• Heart attack
• Stroke
• Chronic kidney disease (occurs in about 66% of PNH patients)
• Lung-associated complications (occurs in about 50% of PNH patients), possibly arising from pulmonary hypertension, leading to shortness of breath

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a progressive disorder and when complications, such as blood clots in the arteries or bleeding are present, it can even lead to death.

How is Paroxysmal Nocturnal Hemoglobinuria Treated?

Paroxysmal Nocturnal Hemoglobinuria is a disorder in which damage occurs to the blood cells, and as a consequence, to different body functions constantly, even in the absence of symptoms or seriously compromised body functions. Therefore, seeking and continuing treatment is imperative to leading a healthy life and avoiding life-threatening health events. It is hence, important to find the right kind of treatment, as early as possible.

The treatment options for Paroxysmal Nocturnal Hemoglobinuria depend on the type and severity of the symptoms. The following are some treatment options available to PNH patients:

• Folic acid and iron supplements for mild anemia
• Steroid treatment to suppress the immune system, so as to help stem the breakdown of red blood cells
• Use of the ‘orphan drug’ Eculizumab (a monoclonal antibody, approved by the US Food and Drug Administration in 2007) to block the breakdown of red blood cells
• Blood transfusion
• Bone marrow transplantation from a compatible donor
• Vaccinations against certain bacterial infections to prevent repeated infections
• The use of blood thinners to help prevent clots

How can Paroxysmal Nocturnal Hemoglobinuria be Prevented?

At this time, no measures that could prevent the onset of Paroxysmal Nocturnal Hemoglobinuria have been reported.

What is the Prognosis of Paroxysmal Nocturnal Hemoglobinuria? (Outcomes/Resolutions)

• The prognosis of Paroxysmal Nocturnal Hemoglobinuria depends on the type/s of blood cells affected and the severity of symptoms
• While some individuals with mild symptoms can manage their condition with supplements, those with more severe symptoms may face life-threatening issues such as bleeding or clot formation
• It is reported that many patients live up to 10 years after diagnosis of PNH

Additional and Relevant Useful Information for Paroxysmal Nocturnal Hemoglobinuria:

• Aplastic anemia is a disorder that occurs due to bone marrow failure

The following article link will help you understand acquired aplastic anemia:

http://www.dovemed.com/diseases-conditions/acquired-aplastic-anemia