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Anaemia and Haemoglobinuria
The Management of Paroxysmal Nocturnal Haemoglobinuria –
Recent Advances in Diagnosis and Treatment, and New Hope for Patients
Hubert Schrezenmeier and Britta Höchsmann
Institute of Transfusion Medicine, University of Ulm, and Institute of Clinical Transfusion Medicine and Immunogenetics, Ulm,
Red Cross Blood Service, Baden-Württemberg-Hessen
Abstract
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare life-threatening and debilitating disorder of haematopoiesis. It is characterised by
the clinical triad of Coombs-negative acquired extracorpuscular haemolytic anaemia, thrombophilia and bone marrow failure. The
sequelae of intravascular haemolysis drastically affect the quality of life of patients. Cytopenia and in particular thrombophilia can cause
life-threatening complications. Thromboembolic events are the major cause of death. The only curative treatment for PNH is allogeneic
stem cell transplantation from a related or unrelated stem cell donor. Recent reports demonstrated favourable outcomes. Other
treatments were generally supportive in nature. Recently, eculizumab, a humanised monoclonal antibody that inhibits complement factor
C5, was approved. It is a targeted, disease-modifying treatment of PNH. This article will summarise major advances in the management
of PNH during the last year and, in particular, will discuss new results of eculizumab, treatment of thrombosis and stem cell
transplantation. Given the new advances there is hope for improved survival of these patients.
Keywords
Paroxysmal nocturnal haemoglobunuria, stem cell transplantation, eculizumab
Disclosure: The authors have no conflicts of interest to declare.
Received: 27 November 2008 Accepted: 18 June 2009
Correspondence: Hubert Schrezenmeier, Chair, Professor of Transfusion Medicine, Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, Red Cross Blood
Service Baden-Württemberg – Hessen and Institute of Transfusion Medicine University of Ulm, Helmholtzstraße 10, 89081 Ulm, Germany. E:
h.schrezenmeier@blutspende.de
Pathophysiology of Paroxysmal PNH and has replaced the Ham test and the sucrose lysis test (sugar
Nocturnal Haemoglobinuria water test).
5,9
Flow cytometry allows sensitive and specific detection of
Paroxysmal nocturnal haemoglobinuria (PNH) is a non-malignant even small GPI-deficient populations and a quantitative assessment of
clonal disorder of haematopoiesis.
1
The genetic basis is acquired the size of the PNH cell population in various cell lineages, and can be
somatic mutations of the X-chromosomal gene PIG-A in one or few used for both initial diagnosis and monitoring during follow-up.
3,4,10–12
haematopoietic stem/progenitor cells.
2
The protein encoded by PIG-A
is essential for the synthesis of the glycosylphosphatidylinositol (GPI) Clinically, PNH is characterised by the triad of acquired Coombs-
anchor. The GPI moiety serves as the membrane anchor for a group of negative intracorpuscular haemolytic anaemia, thrombophilia and
proteins, known as GPI-anchored proteins. These proteins are bone marrow failure.
1,9,13
The clinical presentation and the course of the
functionally diverse, and include CD14, CD16, CD24, CD28, CD48, disease are highly variable. Many of the clinical features of PNH can be
CD52, CD55, CD58, CD59, CD66c, CD66b, CD73, CD87, CD90, CD108, attributed to the deficiency of the GPI-anchored proteins: two GPI-
CD109, CD157, CD317, GP500, GP175 and JMH-bearing protein.
3–5
The anchored proteins (CD55, CD59) are important for regulation of
expression of these proteins is either substantially reduced (PNH type complement. Absence of these proteins from the surface of PNH red
II cells) or completely missing (PNH type III cells) on the cells arising blood cells (RBCs) renders them susceptible to terminal complement-
from the PIG-A mutated stem or progenitor cell (see Figure 1). As mediated lysis. CD59 blocks the terminal complement complex
PIG-A gene mutations in PNH are acquired somatic mutations, not all (membrane attack complex). Due to the absence of CD55 and CD59,
haematopoietic cells are affected. There is always a mosaic of PNH RBCs are highly sensitive to complement-mediated haemolysis.
PIG-A-mutated, GPI-deficient cells and non-PIG-A-mutated cells with Severe haemolysis occurs predominantly in situations where
normal expression of GPI-anchored proteins (see Figure 1).
2
complement activation is enhanced, thus in most instances these
Interestingly, clonal populations of haematopoietic cells with PIG-A haemolytic crises occur in the context of infections, surgery, trauma or
gene mutation and GPI-anchor deficiency are also present in normal pregnancy. Chronic haemolysis with haemosiderinuria leads to iron
individuals.
6,7
Selection of GPI-anchor-deficient cells or secondary deficiency in many patients.
14,15
genetic events in PIG-A-mutated cells might be necessary for the
expansion of the PNH clone(s).
8
Thrombophilia is the leading cause of mortality in PNH. Thrombosis
in PNH will occur in about 50% of patients with haemolytic
Measurement of expression of the GPI-anchored proteins by flow PNH.
9,13,16,17
Thrombosis can occur anywhere; however, it often occurs
cytometry has become the gold standard for laboratory diagnosis of at ‘unusual’ sites such as hepatic, portal, splenic and mesenteric,
12 © TOUCH BRIEFINGS 2009
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