Paroxysmal nocturnal hemoglobinuria
Encyclopedia
Paroxysmal nocturnal hemoglobinuria (PNH), sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterised by complement-induced intravascular hemolytic anemia
(anemia due to destruction of red blood cell
s in the bloodstream), red urine
(due to the appearance of hemoglobin
in the urine) and thrombosis
. PNH is the only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the cell membrane
(deficiency of glycophosphatidylinositol
leading to absence of protective proteins on the membrane). 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 have the telltale red urine in the morning.
Allogeneic bone marrow transplantation
is the only curative therapy, although the monoclonal antibody eculizumab
(Soliris) is effective at reducing the need for blood transfusions, improving quality of life, and reducing the risk of thrombosis.
and hemosiderin
) may be identified. A small proportion of patients report abdominal pain, dysphagia
(difficulty swallowing) and odynophagia
(pain during swallowing), as well as erectile dysfunction
in men - this occurs mainly when the breakdown of red blood cells is rapid.
Forty percent of patients 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 veins 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 PNH.
s in PNH show changes consistent with intravascular hemolytic anemia
: low hemoglobin
, raised lactate dehydrogenase
, raised reticulocyte
s (immature red cells released by the bone marrow
to replace the destroyed cells), raised bilirubin
(a breakdown product of hemoglobin), and decreased levels of haptoglobin
. The direct antiglobulin test (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by antibodies
.
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 (after Dr Thomas Ham, who described the test in 1937) test was performed for confirmation.
Today, many labs use 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 flow cytometry for CD59 or CD55.
The enzyme phosphatidylinositol glycan A (PIGA) is needed to make glycosylphosphatidylinositol (GPI), a molecule that anchors proteins to the cell membrane. 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
). If a mutation occurs in this gene then PIGA may be defective, which leads to a defect in the GPI anchor. When this mutation occurs in a bone marrow
stem cell
(which are used to make red blood cells as well as white blood cells and platelets), all of the cells it produces will also have the defect. 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. The complement system is part of the immune system
and helps to destroy invading microorganisms. Without the proteins that protect them from complement, red blood cells are destroyed. The main proteins that carry out this function are the decay-accelerating factor (DAF) (CD55), which disrupts formation of C3 convertase, and protectin (CD59
), which binds the membrane attack complex and prevents C9
from binding to the cell.
The increased destruction of red blood cells results in anemia. The increased rate of thrombosis is due to dysfunction of platelet
s due to binding by complement
, or possibly due to low nitric oxide
levels.
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. 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.
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.
) 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.
A new monoclonal antibody, eculizumab
, protects blood cells against immune destruction by inhibiting the complement system
. It has been shown to reduce the need for blood transfusion in patients with significant hemolysis.
. 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.
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).
physician Paul Strübing (Greifswald
, 1852–1915) in 1882. A more detailed description was made by Dr Ettore Marchiafava and Dr Alessio Nazari in 1911, with further elaborations by Marchiafava in 1928 and Dr Ferdinando Micheli in 1931. The Dutch physician Enneking coined the term "paroxysmal nocturnal hemoglobinuria" (or haemoglobinuria paroxysmalis nocturia in Latin) in 1928.
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
(anemia due to destruction of red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s in the bloodstream), red urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
(due to the appearance of hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
in the urine) and thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
. PNH is the only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
(deficiency of glycophosphatidylinositol
Glycophosphatidylinositol
Glycosylphosphatidylinositol is a glycolipid that can be attached to the C-terminus of a protein during posttranslational modification...
leading to absence of protective proteins on the membrane). It may develop on its own ("primary PNH") or in the context of other bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
disorders such as aplastic anemia
Aplastic anemia
Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia...
("secondary PNH"). Only a minority have the telltale red urine in the morning.
Allogeneic bone marrow transplantation
Allogeneic bone marrow transplantation
Allogeneic bone marrow transplantation is a procedure in which a person receives stem cells from a genetically similar, but not identical, donor.- External links :...
is the only curative therapy, although the monoclonal antibody eculizumab
Eculizumab
Eculizumab is a monoclonal antibody directed against the complement protein C5. Eculizumab has been shown to be effective in treating paroxysmal nocturnal hemoglobinuria , a rare and sometimes life threatening disease of the blood, and is approved for this indication.Eculizumab is a recombinant...
(Soliris) is effective at reducing the need for blood transfusions, improving quality of life, and reducing the risk of thrombosis.
Signs and symptoms
Most people with "primary PNH" have red urine at some point in their disease course. Many of them continue to have low-grade breakdown of red blood cells, leading to anemia. Typical symptoms of anemia are tiredness, shortness of breath, and palpitations. On laboratory examination of the urine, breakdown products of red blood cells (hemoglobinHemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
and hemosiderin
Hemosiderin
thumb|Hemosiderin image of a kidney viewed under a microscope. The brown areas represent hemosiderinHemosiderin or haemosiderin is an iron-storage complex. It is always found within cells and appears to be a complex of ferritin, denatured ferritin and other material...
) may be identified. A small proportion of patients report abdominal pain, dysphagia
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
(difficulty swallowing) and odynophagia
Odynophagia
Odynophagia is painful swallowing, in the mouth or esophagus. It can occur with or without dysphagia, or difficult swallowing....
(pain during swallowing), as well as erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
in men - this occurs mainly when the breakdown of red blood cells is rapid.
Forty percent of patients develop thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
(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
Deep vein thrombosis
Deep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
of the leg veins and resultant pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
when these clots break off and enter the lungs), but, in PNH, blood clots may also form in more unusual sites: the hepatic vein
Hepatic vein
In human anatomy, the hepatic veins are the blood vessels that drain de-oxygenated blood from the liver and blood cleaned by the liver into the inferior vena cava....
(causing Budd-Chiari syndrome
Budd-Chiari syndrome
In medicine , Budd–Chiari syndrome is the clinical picture caused by occlusion of the hepatic veins. It presents with the classical triad of abdominal pain, ascites and hepatomegaly. Examples of occlusion include thrombosis of hepatic veins. The syndrome can be fulminant, acute, chronic, or...
), the portal vein of the liver (causing portal vein thrombosis
Portal vein thrombosis
Portal vein thrombosis is a form of venous thrombosis affecting the hepatic portal vein, which can lead to portal hypertension and reduction in the blood supply to the liver.-Causes:...
), the superior
Superior mesenteric vein
In anatomy, the superior mesenteric vein is a blood vessel that drains blood from the small intestine . At its termination behind the neck of the pancreas, the SMV combines with the splenic vein to form the hepatic portal vein...
or inferior mesenteric vein
Inferior mesenteric vein
In human anatomy, the inferior mesenteric vein is a blood vessel that drains blood from the large intestine. It usually terminates when reaching the splenic vein, which goes on to form the portal vein with the superior mesenteric vein...
(causing mesenteric ischemia
Mesenteric ischemia
Mesenteric ischemia is a medical condition in which inflammation and injury of the small intestine result from inadequate blood supply. Causes of the reduced blood flow can include changes in the systemic circulation or local factors such as constriction of blood vessels or a blood clot...
), and veins of the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
. Cerebral venous thrombosis, an uncommon form of stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, is more common in PNH.
Diagnosis
Blood testBlood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
s in PNH show changes consistent with intravascular hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
: low hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
, raised lactate dehydrogenase
Lactate dehydrogenase
Lactate dehydrogenase is an enzyme present in a wide variety of organisms, including plants and animals.Lactate dehydrogenases exist in four distinct enzyme classes. Two of them are cytochrome c-dependent enzymes, each acting on either D-lactate or L-lactate...
, raised reticulocyte
Reticulocyte
Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in the human body.Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells,...
s (immature red cells released by the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
to replace the destroyed cells), raised bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
(a breakdown product of hemoglobin), and decreased levels of haptoglobin
Haptoglobin
Haptoglobin is a protein that in humans is encoded by the HP gene. In blood plasma, haptoglobin binds free hemoglobin released from erythrocytes with high affinity and thereby inhibits its oxidative activity. The haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system...
. The direct antiglobulin test (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
.
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 (after Dr Thomas Ham, who described the test in 1937) test was performed for confirmation.
Today, many labs use flow cytometry
Flow cytometry
Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...
for CD55 and CD59
CD59
Protectin, a complement regulatory protein, also known as ', or MIRL is a human gene and protein....
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
Fluorescein-labeled proaerolysin
Fluorescein-labeled proaerolysin is a flow cytometric assay used to diagnose paroxysmal nocturnal hemoglobinuria . The assay takes advantage of the action of proaerolysin, a prototoxin of aerolysin, a virulence factor of the bacterium Aeromonas hydrophila. Proaerolysin binds to the...
(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 flow cytometry 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.
- Subclinical PNH. PNH abnormalities on flow cytometry without signs of hemolysis.
Pathophysiology
All cells have proteins attached to their membranes that are responsible for performing a vast array of functions. There are several ways for proteins to be attached to a cell membrane. PNH occurs as a result of a defect in one of these mechanisms.The enzyme phosphatidylinositol glycan A (PIGA) is needed to make glycosylphosphatidylinositol (GPI), a molecule that anchors proteins to the cell membrane. The gene that codes for PIGA is located on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
, 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
X-inactivation
X-inactivation is a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin...
). If a mutation occurs in this gene then PIGA may be defective, which leads to a defect in the GPI anchor. When this mutation occurs in a bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
(which are used to make red blood cells as well as white blood cells and platelets), all of the cells it produces will also have the defect. Several of the proteins that anchor to GPI on the cell membrane are used to protect the cell from destruction by the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
, and, without these anchors, the cells are more easily targeted by the complement proteins. The complement system is part of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
and helps to destroy invading microorganisms. Without the proteins that protect them from complement, red blood cells are destroyed. The main proteins that carry out this function are the decay-accelerating factor (DAF) (CD55), which disrupts formation of C3 convertase, and protectin (CD59
CD59
Protectin, a complement regulatory protein, also known as ', or MIRL is a human gene and protein....
), which binds the membrane attack complex and prevents C9
Complement component 9
Complement component 9 is a protein involved in the complement system....
from binding to the cell.
The increased destruction of red blood cells results in anemia. The increased rate of thrombosis is due to dysfunction of platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s due to binding by complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
, or possibly due to low nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
levels.
The symptoms of esophageal spasm, erectile dysfunction, and abdominal pain are attributed to the fact that hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
released during hemolysis binds with circulating nitric oxide, a substance that is needed to relax smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
. This theory is supported by the fact that these symptoms improve on administration of nitrates or sildenafil
Sildenafil
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
(Viagra), which improves the effect of nitric oxide on muscle cells. There is a suspicion that chronic hemolysis causing chronically depleted nitric oxide may lead to the development of pulmonary hypertension
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
(increased pressure in the blood vessels supplying the lung), which in turn puts strain on the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
and causes heart failure.
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, preventative treatment with warfarinWarfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
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
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
or similar drugs needs to be continued long-term after an episode of thrombosis.
Acute attacks
There is disagreement as to whether steroids (such as prednisolonePrednisolone
Prednisolone is the active metabolite of prednisone, which is also used as a drug.-Uses:Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as...
) can decrease the severity of hemolytic crises. Transfusion therapy may be needed; in addition to correcting significant anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, 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.
A new monoclonal antibody, eculizumab
Eculizumab
Eculizumab is a monoclonal antibody directed against the complement protein C5. Eculizumab has been shown to be effective in treating paroxysmal nocturnal hemoglobinuria , a rare and sometimes life threatening disease of the blood, and is approved for this indication.Eculizumab is a recombinant...
, protects blood cells against immune destruction by inhibiting the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
. It has been shown to reduce the need for blood transfusion in patients with significant hemolysis.
Screening
Screening for PNH is performed every year in people with previous aplastic anemia, and may be performed in people with myelodysplastic syndrome of the "refractory anemia" type.Epidemiology
PNH is rare, with an annual rate of 1-2 cases per million. Many cases develop in people who have previously been diagnosed with aplastic anemia or myelodysplastic syndromeMyelodysplastic syndrome
The myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....
. The fact that PNH develops in MDS also explains why there appears to be a higher rate of leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
in PNH, as MDS can sometimes transform into leukemia.
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).
History
The first description of paroxysmal hemoglobinuria was by the GermanGermany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
physician Paul Strübing (Greifswald
Greifswald
Greifswald , officially, the University and Hanseatic City of Greifswald is a town in northeastern Germany. It is situated in the state of Mecklenburg-Vorpommern, at an equal distance of about from Germany's two largest cities, Berlin and Hamburg. The town borders the Baltic Sea, and is crossed...
, 1852–1915) in 1882. A more detailed description was made by Dr Ettore Marchiafava and Dr Alessio Nazari in 1911, with further elaborations by Marchiafava in 1928 and Dr Ferdinando Micheli in 1931. The Dutch physician Enneking coined the term "paroxysmal nocturnal hemoglobinuria" (or haemoglobinuria paroxysmalis nocturia in Latin) in 1928.