Paroxysmal nocturnal hemoglobinuria

Synonyms

2

Overview

Paroxysmal nocturnal hemoglobinuria (or paroxysmal nocturnal haemoglobinuria (PNH), previously Marchiafava–Micheli syndrome), is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's intrinsic immune system. This destructive process is a result of a defect in the formation of surface proteins on the red blood cell, which normally function to inhibit such immune reactions. Since the complement cascade attacks the red blood cells throughout the circulatory system, the hemolysis is considered an intravascular hemolytic anemia. Other key features of the disease, notably the high incidence of thrombosis, are not totally understood.

Symptoms

The classic sign of PNH is red discoloration of the urine due to the presence of hemoglobin and hemosiderin from the breakdown of red blood cells. As the urine is more concentrated in the morning, this is when the color is most pronounced. This phenomenon mainly occurs in those who have the primary form of PNH, who will notice this at some point in their disease course. The remainder mainly experience the symptoms of anemia, such as tiredness, shortness of breath, and palpitations.

A small proportion of patients report attacks of abdominal pain, difficulty swallowing and pain during swallowing, as well as erectile dysfunction in men; this occurs mainly when the breakdown of red blood cells is rapid, and is attributable to spasm of smooth muscle due to red cell breakdown products.

Forty percent of people with PNH develop thrombosis (a blood clot) at some point in their illness. This is the main cause of severe complications and death in PNH. These may develop in common sites (deep vein thrombosis of the leg and resultant pulmonary embolism when these clots break off and enter the lungs), but in PNH blood clots may also form in more unusual sites: the hepatic vein (causing Budd-Chiari syndrome), the portal vein of the liver (causing portal vein thrombosis), the superior or inferior mesenteric vein (causing mesenteric ischemia) and veins of the skin. Cerebral venous thrombosis, an uncommon form of stroke, is more common in those with PNH.

Causes

Mutations in the PIGA gene cause paroxysmal nocturnal hemoglobinuria.

The PIGA gene provides instructions for making a protein called phosphatidylinositol glycan class A. This protein takes part in a series of steps that produce a molecule called GPI anchor. GPI anchor attaches many different proteins to the cell membrane, thereby ensuring that these proteins are available when needed at the surface of the cell.

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. In people with paroxysmal nocturnal hemoglobinuria, somatic mutations of the PIGA gene occur in blood-forming cells called hematopoietic stem cells, which are found mainly in the bone marrow. These mutations result in the production of abnormal blood cells. As the abnormal hematopoietic stem cells multiply, increasing numbers of abnormal blood cells are formed, alongside normal blood cells produced by normal hematopoietic stem cells.

Prevention

There is no known way to prevent this disorder.

Diagnosis

Blood tests in PNH show changes consistent with intravascular hemolytic anemia: low hemoglobin, raised lactate dehydrogenase, raised bilirubin (a breakdown product of hemoglobin), and decreased levels of haptoglobin; there can be raised reticulocytes (immature red cells released by the bone marrow to replace the destroyed cells) if there is no iron deficiency present. Thedirect antiglobulin test (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by antibodies. If the PNH occurs in the setting of known (or suspected) aplastic anemia, abnormal white blood cell counts and decreased platelet counts may be seen at this. In this case, anemia may be caused by insufficient red blood cell production in addition to the hemolysis.

Historically, the sucrose lysis test, in which a patient's red blood cells are placed in low-ionic-strength solution and observed for hemolysis, was used for screening. If this was positive, theHam's acid hemolysis test (after Dr Thomas Ham, who described the test in 1937) was performed for confirmation. The Ham test involves placing red blood cells in mild acid; a positive result (increased RBC fragility) indicates PNH or Congenital dyserythropoietic anemia. This is now an obsolete test for diagnosing PNH due to its low sensitivity and specificity.

Today, the gold standard is flow cytometry for CD55 and CD59 on white and red blood cells. Based on the levels of these cell proteins, erythrocytes may be classified as type I, II, or III PNH cells. Type I cells have normal levels of CD55 and CD59; type II have reduced levels; and type III have absent levels. The fluorescein-labeled proaerolysin (FLAER) test is being used more frequently to diagnose PNH. FLAER binds selectively to the glycophosphatidylinositol anchor and is more accurate in demonstrating a deficit than simply for CD59 or CD55.

Classification:

PNH is classified by the context under which it is diagnosed:

  • Classic PNH. Evidence of PNH in the absence of another bone marrow disorder.
  • PNH in the setting of another specified bone marrow disorder such as aplastic anemia and mylodylastic syndrome (MDS).
  • Subclinical PNH. PNH abnormalities on flow cytometry without signs of hemolysis.

Prognosis

The outcome varies. Most people survive greater than 10 years after their diagnosis. Death can result from complications such as blood clot formation (thrombosis) or bleeding. In rare cases, the abnormal cells may decrease over time.

Possible Complications:

  • Acute myelogenous leukemia
  • Aplastic anemia
  • Blood clots
  • Death
  • Hemolytic anemia
  • Iron deficiency anemia
  • Myelodysplasia

Treatment

Acute attacks

There is disagreement as to whether steroids (such as prednisolone) can decrease the severity of hemolytic crises. Transfusion therapy may be needed; in addition to correcting significant anemia, this suppresses the production of PNH cells by the bone marrow, and indirectly the severity of the hemolysis. Iron deficiency develops with time, due to losses in urine, and may have to be treated if present. Iron therapy can result in more hemolysis as more PNH cells are produced.

Long-term

PNH is a chronic condition. In patients with only a small clone and few problems, monitoring of the flow cytometry every six months gives information on the severity and risk of potential complications. Given the high risk of thrombosis in PNH, preventive treatment with warfarin decreases the risk of thrombosis in those with a large clone (50% of white blood cells type III).

Episodes of thrombosis are treated as they would in other patients, but, given that PNH is a persisting underlying cause, it is likely that treatment with warfarin or similar drugs needs to be continued long-term after an episode of thrombosis.
Approved therapies: 

  • Eculizumab (Soliris) - FDA-approved indication: Treatment of paroxysmal nocturnal hemoglobinuria to reduce hemolysis 

Resources

Refer to Research Publication.