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 anemiaHemolytic 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 cellRed 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
urineUrine 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
hemoglobinHemoglobin 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
thrombosisThrombosis 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 membraneThe 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
glycophosphatidylinositolGlycosylphosphatidylinositol 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 marrowBone 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 anemiaAplastic 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 transplantationAllogeneic 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
eculizumabEculizumab 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 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
hemosiderinthumb|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,
dysphagiaDysphagia 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
odynophagiaOdynophagia 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 dysfunctionErectile 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
thrombosisThrombosis 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 thrombosisDeep 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 embolismPulmonary 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 veinIn 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 syndromeIn 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 thrombosisPortal 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
superiorIn 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 veinIn 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 ischemiaMesenteric 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-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
strokeA 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 testA 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 anemiaHemolytic 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
hemoglobinHemoglobin 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 dehydrogenaseLactate 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
reticulocyteReticulocytes 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 marrowBone 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
bilirubinBilirubin 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
haptoglobinHaptoglobin 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
antibodiesAn 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 cytometryFlow 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
CD59Protectin, 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 proaerolysinFluorescein-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 chromosomeThe 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-inactivationX-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 marrowBone 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 cellThis 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 systemThe 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 systemAn 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 (
CD59Protectin, a complement regulatory protein, also known as ', or MIRL is a human gene and protein....
), which binds the membrane attack complex and prevents
C9Complement 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
plateletPlatelets, 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
complementThe 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 oxideNitric 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
hemoglobinHemoglobin 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 muscleSmooth 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
sildenafilSildenafil 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 hypertensionIn 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
heartThe 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 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
warfarinWarfarin 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 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
anemiaAnemia 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,
eculizumabEculizumab 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 systemThe 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 syndromeThe 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
leukemiaLeukemia 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 , 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 (
GreifswaldGreifswald , 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.
External links