Schrezenmeier.qxp 11/8/09 10:18 am Page 13
The Management of Paroxysmal Nocturnal Haemoglobinuria
Figure 1: Flow Cytometric Analysis of Expression of Glycosylphosphatidylinositol-anchored
Proteins on Granulocytes
Granulocytes Healthy control Small PNH cell population Large PNH cell population
350
300
200
99.52%
280
99.86%
240
160
99.5%
Isotype control
M1
210
180
M1 120 M1
Counts 120 Counts
140
Counts 80
60
70
40
0 0 0
10
0
10
1
10
2
10
3
10
4
10
0
10
1
10
2
10
3
10
4
10
0
10
1
10
2
10
3
10
4
IgG FITC IgG FITC IgG FITC
GPI marker 350
180
150
280 0.03% 11.54% 99.24%
M1
120
210 M1
M1
CD24+CD66b
90
deficiency
Counts
140
Counts
60
Counts
70
30
0 0 0
10
0
10
1
10
2
10
3
10
4
10
0
10
1
10
2
10
3
10
4
10
0
10
1
10
2
10
3
10
4
(CD24+CD66B) FITC (CD24+CD66B) FITC (CD24+CD66B) FITC
GPI marker
350
350
200
0.09%
280
9.66%
280
180
92.56%
M1
210
210
M1
120
M1
CD16
deficiency
Counts 140 Counts
140
Counts 80
70
70
40
0 0 0
10
0
10
1
10
2
10
3
10
4
10
0
10
1
10
2
10
3
10
4
10
0
10
1
10
2
10
3
10
4
CD16 FITC CD16 FITC CD16 FITC
Normal control (left column) and patients with small (middle column) or large glycosylphosphatidylinositol (GPI)-deficient cell population (left column). PNH = paroxysmal nocturnal
haemoglobinuria; IgG = immunoglobulin G; FITC = fluorescein isothiocyanate.
cerebral and dermal veins.
9,16
The risk of thromboembolic events dysphagia, erectile dysfunction and pulmonary hypertension.
seems to be directly related to the size of the PNH cell population NO depletion also increases platelet aggregation, inhibits
(as measured by GPI-deficient granulocytes).
12,16,18
In the study of disaggregation of aggregated platelets and induces platelet
Moyo et al., the odds ratio for risk of thrombosis was estimated to adhesion, which together with local vasoconstriction contribute to
be 1.64 according to logistic regression modelling for a 10% change thrombophilia (see Figure 2). Recent studies have demonstrated
in PNH clone size.
12
No patient with <61% PNH granulocytes that there is a high incidence of progression to chronic
developed a thrombosis, whereas 12 of 22 patients (54.5%) with renal insufficiency in patients with PNH. Renal damage in PNH
≥61% PNH granulocytes manifested with thrombosis.
12
In the study has been associated with chronic haemolysis and subsequent
by Hall et al., the 10-year risk of thrombosis was 5.8% in patients haemosiderosis and/or microvascular thrombosis.
25
with <50% GPI-deficient granulocytes versus 44% in patients with
>50% GPI-deficient granulocytes.
16
The cause of thrombophilia in
PNH is multifactorial (see Table 1).
19
The scavenging of nitric oxide
The scavenging of nitric oxide by
(NO) by free haemoglobin is a crucial event,
20
contributing to both
thrombosis and other PNH-related symptoms. Haemoglobin
free haemoglobin is a crucial event,
released from RBCs during haemolysis binds to haptoglobin, which
contributing to both thrombosis
is rapidly cleared from the circulation via binding to CD163.
21
When
the capacity of this haemoglobin-scavenging protein is saturated,
and other paroxysmal nocturnal
free haemoglobin appears in the circulation and reacts with NO to
haemoglobinuria-related symptoms.
produce nitrate (NO
3
) and methemoglobin.
22
In addition, haemolysis
releases arginase from RBCs.
23
This enzyme converts L-arginine, the
substrate for NO synthesis, to ornithine. A profound degree of NO Progressive pancytopenia occurs in a proportion of PNH patients.
consumption has been demonstrated in PNH patients.
24
NO is a In a recent study of a large cohort of patients in France, the
major regulator of smooth-muscle tonus, influences platelet cumulative 10-year incidence of bicytopenia or pancytopenia was
function and interacts with components of the coagulation 19.2%.
9
In contrast, a substantial proportion of patients (30–50%)
cascade.
25
Decreased NO signalling via cyclic guanosine who were initially diagnosed with otherwise typical aplastic
monophosphate (cGMP) leads to increased smooth-muscle tonus, anaemia (AA) have small proportions of GPI-deficient cells.
26–28
In a
which can result in typical symptoms of PNH, e.g. abdominal pain, long-term follow-up of a cohort of AA patients, the cumulative
EUROPEAN HAEMATOLOGY 13
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