Paroxysmal nocturnal hemoglobinuria

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.[10] 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.[4]

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 depletion of nitric oxide by red cell breakdown products.[11]

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.[4]

CD55 protein/Decay Accelerating Factor structure

CD59 protein/Protectin structure

All cells have proteins attached to their membranes, often serving as a mode of communication or signaling between the cell and the surrounding environment. These signaling proteins are physically attached to the cell membrane in various ways, commonly anchored by glycolipids such as glycosyl phosphatidylinositols (GPI). PNH occurs as a result of a defect in the assembling of these glycolipid-protein structures on the surface of blood cells.[4]

The most common defective enzyme in PNH is phosphatidylinositol glycan A (PIGA), one of several enzymes needed to make GPI. The gene that codes for PIGA is located on the X chromosome, which means that only one active copy of the gene for PIGA is present in each cell (initially, females have two copies, but one is silenced through X-inactivation).[1] A mutation in the PIGA gene can lead to the absence of GPI anchors expressed on the cell membrane. When this mutation occurs in a hematopoietic stem cell in the bone marrow, all of the cells it produces will also have the defect.[4]

Several of the proteins that anchor to GPI on the cell membrane are used to protect the cell from destruction by the complement system, and, without these anchors, the cells are more easily targeted by the complement proteins.[3] Although red blood cells, white blood cells, and platelets are targeted by complement, red blood cells are particularly vulnerable to lysis.[12] 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.[4]

The symptoms of esophageal spasm, erectile dysfunction, and abdominal pain are attributed to the fact that hemoglobin released during hemolysis binds with circulating nitric oxide, a substance that is needed to relax smooth muscle. This theory is supported by the fact that these symptoms improve on administration of nitrates or sildenafil (Viagra), which improves the effect of nitric oxide on muscle cells.[4] There is a suspicion that chronic hemolysis causing chronically depleted nitric oxide may lead to the development of pulmonary hypertension (increased pressure in the blood vessels supplying the lung), which in turn puts strain on the heart and causes heart failure.[13]

Historically, the role of sleep and night in this disease (the "nocturnal" component of the name) has been attributed to acidification of the blood at night due to relative hypoventilation and accumulation of carbon dioxide in the blood during sleep. This hypothesis has been questioned by researchers who note that not all those with PNH have increased hemolysis during sleep, so it is uncertain how important a role sleep actually plays in this disease.[14]

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. The direct antiglobulin test (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by antibodies.[4] 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.[4]

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, the Ham's acid hemolysis test (after Dr Thomas Ham, who described the test in 1937) was performed for confirmation.[5][15] 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.[4] 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.[5]

There are several groups where screening for PNH should be undertaken. These include patients with unexplained thrombosis who are young, have thrombosis in an unusual site (e.g. intra-abdominal veins, cerebral veins, dermal veins), have any evidence of hemolysis (e.g. a raised LDH), or have a low red blood cell, white blood cell, or platelet count.[16] Those who have a diagnosis of aplastic anemia should be screened annually.[4]

PNH is rare, with an annual rate of 1-2 cases per million.[4] The prognosis without disease-modifying treatment is 10–20 years.[22] Many cases develop in people who have previously been diagnosed with aplastic anemia or myelodysplastic syndrome. 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.[4]

25% of female cases of PNH are discovered during pregnancy. This group has a high rate of thrombosis, and the risk of death of both mother and child are significantly increased (20% and 8% respectively).[4]

The first description of paroxysmal hemoglobinuria was by the German physician Paul Strübing (Greifswald, 1852–1915) during a lecture in 1881, later published in 1882.[23] Later comprehensive descriptions were made by Ettore Marchiafava and Alessio Nazari in 1911,[24] with further elaborations by Marchiafava in 1928[25] and Ferdinando Micheli in 1931.[26][27]

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.[28]