Paroxysmal nocturnal hemoglobinuria (PNH) 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 innate immune system. This destructive process occurs due to deficiency of the red blood cell surface protein DAF, which normally inhibits such immune reactions. Since the complement cascade attacks the red blood cells within the blood vessels of the circulatory system, the red blood cell destruction (hemolysis) is considered an intravascular hemolytic anemia. There is ongoing research into other key features of the disease, such as the high incidence of venous blood clot formation. Research suggests that PNH thrombosis (a blood clot) is caused by both the absence of GPI-anchored complement regulatory proteins (CD55 and CD59) on PNH platelets and the excessive consumption of nitric oxide (NO).
PNH is the only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the cell membrane (deficiency of glycophosphatidylinositol or GPI) leading to the absence of protective exterior surface proteins that normally attach via a GPI anchor. It may develop on its own ("primary PNH") or in the context of other bone marrow disorders such as aplastic anemia ("secondary PNH"). Only a minority of affected people have the telltale red urine in the morning that originally gave the condition its name.
Allogeneic bone marrow transplantation is the only cure, but has significant rates of additional medical problems and the risk of death. Eculizumab dramatically alters the natural course of PNH, reducing symptoms and disease complications as well as improving survival to the extent that it may be equivalent to that of the general population.
Signs and 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 fatigue, shortness of breath, and palpitations.
Forty percent of people with PNH develop thrombosis 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. The complement system is part of the innate immune system and has a variety of functions, from destroying invading microorganisms by opsonization to direct destabilization by the membrane attack complex. The main proteins that protect blood cells from destruction are decay-accelerating factor (DAF/CD55), which disrupts formation of C3-convertase, and protectin (CD59/MIRL/MAC-IP), which binds the membrane attack complex and prevents C9 from binding to the cell.
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 concurrent problem with production of red cells (such as iron deficiency). The direct antiglobulin test (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by antibodies. 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. Those who have a diagnosis of aplastic anemia should be screened annually.
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. Many cases develop in people who have previously been diagnosed with myelodysplastic syndrome (MDS). The fact that PNH develops in MDS also explains why there appears to be a higher rate of leukemia in PNH, as MDS can sometimes transform into leukemia or aplastic anemia. Later comprehensive descriptions were made by Ettore Marchiafava and Alessio Nazari in 1911, with further elaborations by Marchiafava in 1928 and Ferdinando Micheli in 1931.
The Dutch physician Enneking coined the term "paroxysmal nocturnal hemoglobinuria" (or haemoglobinuria paroxysmalis nocturna in Latin) in 1928, which has since become the default description. Historically, the term Marchiafava Micheli syndrome has been used.
Society and culture
Economics
Eculizumab costs at least US$440,000 for a single year of treatment and has been reported as one of the world's most expensive drugs.