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Encyclopedia > Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired life-threatening disease of the blood characterised by hemolytic anemia, thrombosis and red urine due to breakdown of red blood cells. PNH is the only hemolytic anemia caused by an acquired intrinsic defect in the cell membrane. Hemolytic anemia is anemia due to hemolysis, the abnormal breakdown of red blood cells either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular). ... Thrombosis is the formation of a clot or thrombus inside a blood vessel, obstructing the flow of blood through the circulatory system. ... This article or section is in need of attention from an expert on the subject. ... Human red blood cells Red blood cells are the most common type of blood cell and the vertebrate bodys principal means of delivering oxygen from the lungs or gills to body tissues via the blood. ... Illustration of a cell membrane The cell membrane, also called the plasma membrane or plasmalemma, is a semipermeable lipid layer surrounding the cytoplasm of all living cells. ...

Contents

Signs and symptoms

Quite paradoxically, the destruction of red blood cells (hemolysis) is neither paroxysmal nor nocturnal the majority of the time (this constellation of symptoms is seen in only 25% of patients). On-going hemolysis is a more common characteristic.


A common finding in PNH is the presence of breakdown products of RBCs (hemoglobin and hemosiderin) in the urine. 3-dimensional structure of hemoglobin. ... Hemosiderin Image of a kidney viewed under a microscope. ...


An inconsistent, but potentially life-threatening, complication of PNH is the development of clot in the veins (venous thrombosis). These clots (thrombi) are often found in the hepatic (causing Budd-Chiari syndrome), portal (causing portal vein thrombosis), and cerebral veins (causing cerebral venous thrombosis). Thrombosis is the formation of a clot or thrombus inside a blood vessel, obstructing the flow of blood through the circulatory system. ... Superior vena cava, inferior vena cava (IVC), azygos vein and their tributaries. ... In medicine (gastroenterology and hepatology), Budd-Chiari syndrome is the clinical picture caused by occlusion of the hepatic vein. ... The portal vein is a major vein in the human body draining blood from the digestive system and its associated glands. ...


Many patients with bone marrow failure (aplastic anemia) develop PNH (10-33%). Aplastic anemia can be caused by an attack by the immune system against the bone marrow. For this reason, drugs that suppress the immune system are being researched as a therapy for PNH. Aplastic anemia is a condition where the bone marrow does not produce enough, or any, new cells to replenish the blood cells. ...


Diagnosis

A sugar or sucrose lysis test, in which a patient's red blood cells are placed in low ionic strength solution and observed for hemolysis, is used for screening. A more specific test for PNH, called Ham's acid hemolysis test, is performed if the sugar test is positive for hemolysis.


Modern methods include flow cytometry for CD55, CD16 and CD59 on white and red blood cells. Dependent on the presence of these molecules on the cell surface, they are classified as type I, II or III PNH cells. Flow cytometry is a technique for counting, examining and sorting microscopic particles suspended in a stream of fluid. ... Decay accelerating factor is a protein involved in the complement system. ... White Blood Cells is also the name of a White Stripes album. ... Human red blood cells Red blood cells are the most common type of blood cell and are the vertebrate bodys principal means of delivering oxygen to body tissues via the blood. ...


Classification

PNH is classified:

  • 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 and they 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.


A molecule called PIGA (phosphatidylinositol glycan A) is needed to make a cell membrane anchor for proteins called GPI (glycosylphosphatidylinositol). The gene that codes for PIGA is inherited in an X-linked fashion, which means that only one active copy of the gene for PIGA may exist. 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. 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 which carry out this function are CD16, CD55 and CD59 (CD is an acronym for cluster of differentiation). Sex linkage is the phenotypic expression of an allele that is dependent on the sex of the individual and is directly tied to the sex chromosomes. ... A GPI anchor (phosphatidyl-inositol glycane) is a common modification of the C-terminus of membrane-attached proteins. ... Grays Anatomy illustration of cells in bone marrow. ... Mouse embryonic stem cells with fluorescent marker. ... A complement protein attacking an invader. ... A scanning electron microscope image of a single human lymphocyte. ... It has been suggested that this article or section be merged with Backronym and Apronym (Discuss) Acronyms and initialisms are abbreviations, such as NATO, laser, and ABC, written as the initial letter or letters of words, and pronounced on the basis of this abbreviated written form. ... The introduction to this article provides insufficient context for those unfamiliar with the subject matter. ...


The increased destruction of red blood cells results in anemia. The increased rate of thrombosis is due to dysfunction of platelets. They are also made by the bone marrow stem cells and will have the same GPI anchor defect as the red blood cells. The proteins which use this anchor are needed for platelets to clot properly, and their absence leads to a hypercoagulable state. A 250 ml bag of newly collected platelets. ...


Treatment

Steroids (such as prednisolone) can decrease the severity of hemolytic crises at moderate dosage (1 mg/kg/day). 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 defficiency develops with time, due to losses in urine, and may have to be treated if present. Iron therapy can results in more hemolysis as more PNH cells are produced, and hence should be given under steroid cover.[citation needed] Androgens like danazol are sometimes effective in steroid refractory disease but side effects can be a problem.[citation needed] The structure of prednisolone Prednisolone is the active metabolite of prednisone. ... Anemia (AmE) or anaemia (BrE), from the Greek () meaning without blood, refers to a deficiency of red blood cells (RBCs) and/or hemoglobin. ...


A new monoclonal antibody, eculizumab, protects blood cells against immune destruction by inhibiting the complement system. Monoclonal antibodies (mAb) are antibodies that are identical because they were produced by one type of immune cell, all clones of a single parent cell. ... Eculizumab is a monoclonal antibody directed against the complement protein C5. ... A complement protein attacking an invader. ...


Animal studies suggest that infusing membrane-targeted CD59 might restore protection against complement-mediated lysis, and is being developed further for use in patients (Hill et al 2006).


Prophylactic use of anticoagulants (warfarin) is used to fight thrombosis. An anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting. ... Warfarin (also known under the brand names of Coumadin®, Jantoven®, Marevan®, and Waran®) is an anticoagulant medication that is administered orally or, very rarely, by injection. ...


In severe aplasia, bone marrow transplants are occasionally undertaken. Bone marrow transplantation or hematopoietic stem cell transplantation (HSCT) is a medical procedure in the field of hematology and oncology that involves transplantation of hematopoietic stem cells (HSC). ...


History

The first description of paroxysmal hemoglobinuria was by the German physician Paul Strübing (1852). 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.


References

  • Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socie G, International PNH Interest Group. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005;106:3699-709. PMID 16051736.
  • Sacher, Ronald A. and Richard A. McPherson. "Wildman's Clinical Interpretation of Laboratory Tests, 11th edition."
  • Kumar, Vinay, Abu Abbas, and Nelson Fausto. "Robbins and Cotran Pathologic Basis of Disease, 7th edition."
  • Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP.Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004;350:552-9. PMID 14762182.
  • Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. PIG-A mutations in normal hematopoiesis. Blood 2005;105:3848-54. PMID 15687243.
  • Hill A, Ridley SH, Esser D, Oldroyd RG, Cullen MJ, Kareclas P, Gallagher S, Smith GP, Richards SJ, White J, Smith RA, Hillmen P. Protection of erythrocytes from human complement-mediated lysis by membrane-targeted recombinant soluble CD59: a new approach to PNH therapy. Blood 2006;107:2131-7. PMID 16322479.
  • Ham TH. Chronic haemolytic anaemia with paroxysmal nocturnal haemoglobinuria: study of the mechanism of haemolysis in relation to acid-base equilibtium. N Engl J Med 1937;217:915-918.
  • Strübing P. Paroxysmale Hämoglobinurie. Dtsch Med Wochenschr 1882;8:1-3 and 17-21.
  • Marchiafava E, Nazari A. Nuovo contributo allo studio degli itteri cronici emolitici. Policlinico [Med] 1911;18:241-254.
  • Marchiafava E. Anemia emolitica con emosiderinuria perpetua. Policlinico [Med] 1928;35:105-117.
  • Micheli F. Uno caso di anemia emolitica con emosiderinuria perpetua. G Accad Med Torino 1931;13:148.
  • Whonamedit entry

Blood is a bimonthly medical journal published by the American Society of Hematology. ... The New England Journal of Medicine (NEJM) is a peer-reviewed medical journal published by the Massachusetts Medical Society. ... The New England Journal of Medicine (NEJM) is a peer-reviewed medical journal published by the Massachusetts Medical Society. ...

External links


  Results from FactBites:
 
eMedicine - Paroxysmal Nocturnal Hemoglobinuria : Article by Emmanuel C Besa (5075 words)
Paroxysmal nocturnal hemoglobinuria (PNH) is a descriptive term for the clinical manifestation of red cell breakdown with release of hemoglobin into the urine that is manifested most prominently by dark-colored urine in the morning.
PNH may occur at any age, from children (10%) as young as 2 years to adults as old as 83 years, but it frequently is found among adults, with a median age at the time of diagnosis of 42 years (range, 16-75 y) from a series in England of 80 consecutive patients.
PNH III cells are markedly sensitive, requiring one fifteenth to one twentieth of complement for an equal degree of lysis.
  More results at FactBites »

 
 

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