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Anaemia and Haemoglobinuria
Table 1: Multifactorial Pathogenesis of the Thrombotic Table 2: Approaches for Treatment of Paroxysmal
Tendency in Paroxysmal Nocturnal Haemoglobinuria Nocturnal Haemoglobinuria
Scavenging of NO by free haemoglobin:
19
Curative Treatment
NO inhibits platelet aggregation/adhesion and induces disaggregation
Allogeneic stem cell transplantation:
(through increasing cGMP levels)
83
Related and unrelated donors, conventional or reduced intensity
NO inhibits factor XIII
25
conditioning (see Tables 3 and 4)
NO reduction leads to increase in fibrinogen split products and
Non-curative Treatment
thrombin–antithrombin complexes
84
Supportive treatment:
Platelet activation by free haemoglobin
85
Red blood cell transfusions (as required based on symptoms)
Inhibition of ADAMTS13 by free haemoglobin
86
Folic acid supplementation
Platelet vesiculation/microvesicles
87,88
Iron replacement (as required based on iron stores)
Increased membrane prothrombinase complex sites; increased rate of
Treatment of complications when they occur, e.g. thrombosis
prothrombin conversion
Prophylactic anticoagulation
Exposure of internal red blood cell membrane
Prevention/early treatment of infections
Increased proportion of activated platelets (due to CD59 deficiency)
89
Non-targeted therapies of PNH-related problems:
Detachment of urokinase-type plasminogen activator receptor (urokinase
Corticosteroids
receptor [CD87] – a GPI-linked protein)
90
and reduced fibrinolytic activity
91
Androgens
NO = nitric oxide; cGMP = cyclic guanosine monophosphate; Haematopoietic growth factors: erythropoiesis-stimulating agents, G-CSF
GPI = glycosylphosphatidylinositol.
High-dose cyclophosphamide
Immunosuppressive Treatment
Figure 2: Consequences of Nitric Oxide Depletion by In AA-PNH syndrome with severe bone marrow failure requiring treatment
Intravascular Haemolysis
Targeted Therapy
Complement inhibition by eculizumab
Depletion of NO
Replacement of complement regulatory proteins on PNH cells (not yet available
for patients)
Gene therapy (not yet available for patients)
PNH = paroxysmal nocturnal hemoglobinuria; G-CSF = granulocyte-colony-stimulating
Reduced NO-mediated signal transduction via cGMP
factor; AA = aplastic anaemia.
complement was a logical approach. Eculizumab, a monoclonal
antibody that inhibits complement protein C5, is the first and so far
Dysregulation of smooth-muscle tonus
Platelet activation Loss of inhibition
only specific complement inhibitor approved for clinical use in PNH.
Platelet aggregation of clotting factors
(FXIII)
Stem cell transplantation and eculizumab treatment will be discussed
in more detail below.
Gastrointestinal
Vasoconstriction
contractions Therapeutic options for PNH are listed in Table 2. Patients with ongoing
haemolysis and erythroid hyperplasia should receive folic acid
Dysphagia Pulmonal hypertension
Abdominal Erectile dysfunction
Thrombosis
supplementation. Iron stores need careful monitoring. Iron repletion,
pain crises Local vasoconstriction
preferentially by oral administration, should be performed.
NO = nitric oxide; cGMP = cyclic guanosine monophosphate.
RBC transfusion should be performed as required based on
symptoms of anaemia. The transfused RBCs are resistant against
incidence of clinical PNH was 13%.
29
Furthermore, multiple complement-mediated lysis. They may even transfer CD55 and CD59
mutations of the PIG-A gene have been demonstrated in patients via microvesicles to the recipient GPI-deficient red cells.
32
Iron overload
with otherwise typical AA.
30
is unlikely in classic haemolytic PNH, but could occur in AA-PNH
syndrome. Transfusion requirements can greatly vary from patient to
In order to reflect the variations in presenting features, clinical patient in the course of the disease (e.g. depending on the frequency
manifestations, and links to other disorders, the International PNH and severity of haemolytic crises due to infections). Leukocyte-reduced
Interest Group (IPIG) proposed to classify the disease as classic RBCs with fewer than 1x10
6
residual leukocytes per unit should be
PNH, PNH in the setting of another specified bone marrow disorder used. Washing of RBCs is not recommended.
33
It is controversial
or subclinical PNH.
1
whether blood products for PNH patients should be irradiated.
Management of Paroxysmal Nocturnal A substantial subgroup of PNH patients has concurrent AA or will
Haemoglobinuria – General Aspects develop AA. Therefore, it must be determined how much of the
Until recently, only two general treatment approaches were available: anaemia is due to haemolysis and how much is due to bone marrow
either stem cell transplantation, which had potential to cure but high failure. Immunosuppressive treatment as established for AA
treatment-related morbidity/mortality, or symptomatic treatment and (antithymocyte globulin, cyclosporine A) can improve the impaired
prophylaxis of complications, which led to unsatisfactory long-term haematopoiesis that occurs in hypoproliferative PNH, but the
control of the disease.
1,31
Thus, there was a need for new treatments haemolytic component of the disease is not altered by
to be developed. As the clinical symptoms of PNH are due to immunosuppressive therapy.
34,35
The effect of immunosuppression on
increased complement sensitivity of blood cells, inhibition of the size of the PNH clone is equivocal. Both expansion and decrease,
14 EUROPEAN HAEMATOLOGY
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