such as BCR and CD40 encounter the re- hances IgM signaling in chronic lymphocytic leukemia.
in chronic lymphocytic leukemia. vation, has been shown in both double-blind
spective ligands, allowing for CLL-cell sur-
vival and clonal propagation. Collectively,
these studies emphasize that prognostic
markers are not an end in itself, but rather
provide keys to a better understanding of the
disease.
Conflict-of-interest disclosure: The author
declares no competing financial interests. ■
REFERENCES
1. Montserrat E. New prognostic markers in CLL (re-
view). Hematology Am Soc Hematol Educ Program. 2006;
279-284.
2. Chen L, Apgar J, Huynh L, et al. ZAP-70 directly en-
● ● ● TRANSFUSION MEDICINE
Comment on Hillmen et al, page 4123
A----------------------------------------------------------------------------------------------------------------
new way to prevent thrombosis?
Wendell F. Rosse DUKE UNIVERSITY
Venous thrombosis is a major problem in paroxysmal nocturnal hemoglobinuria
(PNH). The studies of Hillmen and colleagues in this issue of Blood show that an
antibody to complement C5, eculizumab (Soliris), markedly inhibits thrombosis in
affected patients.
lthough some studies show that antico-
A agulation can prevent thrombosis in
some cases of PNH, most experts agree that
once thrombosis has occurred, it is likely to
progress or to recur despite adequate antico-
agulation. A better prophylaxis and treatment
is needed.
The study by Hillmen and colleagues pub-
lished in this issue of Blood may provide the
answer.
The tendency of patients with PNH to suffer
thrombosis was first noted in the 1930s and was
emphasized by Crosby in the early 1950s.1 It has
since been recognized as a major part of the syn-
drome and has been marked in several epidemio-
logical studies as a very bad prognostic sign and
the most common cause of death in PNH. About
30% to 40% of patients of European origin have
serious thrombosis at some time; for unexplained
reasons, only 5% to 10% of patients of East
Asian (Chinese, Japanese, and Thai) or Mexican
origin develop this complication.2,3
The reason for this propensity is not en-
tirely clear. Intravascular hemolysis may
provide altered membrane surfaces upon
which coagulation may be initiated. More
likely, it is the effect of the activation of
complement on platelets and perhaps endo-
blood 1 D E C E M B E R 2 0 0 7 I V O L U M E 1 1 0 , N U M B E R 1 2
Blood. 2005;105:2036-2041.
3. Damle RN, Temburni S, Calissano C, et al. CD38 ex-
pression labels an activated subset within chronic lympho-
cytic leukemia clones enriched in proliferating B cells.
Blood. 2007; 110:3352-3359.
4. Burger JA, Burger M, Kipps TJ. Chronic lymphocytic
leukemia B cells express functional CXCR4 chemokine re-
ceptors that mediate spontaneous migration beneath bone
marrow stromal cells. Blood. 1999;94:3658-3667.
5. Burger JA, Burkle A. The CXCR4 chemokine receptor
in acute and chronic leukaemia: a marrow homing receptor
and potential therapeutic target. Br J Haematol. 2007;137:
288-296.
6. Richardson SJ, Matthews C, Catherwood MA, et al.
ZAP-70 expression is associated with enhanced ability to
respond to migratory and survival signals in B-cell chronic
lymphocytic leukemia (B-CLL). Blood. 2006;107:3584-
3592.
thelial cells. In platelets, the deposition of
C9 complexes on the surface stimulates their
removal by vesiculation; these vesicles are
very thrombogenic. Because PNH platelets
lack the mechanism for downregulating C9
deposition (ie, CD59), even a minimal
stimulus from activated complement results
in a greatly increased production of these
vesicles.
The drug eculizumab, a humanized mono-
clonal antibody against C5 inhibiting its acti-
● ● ● HEMOSTASIS
Comment on Oh, page 3891
Novel player in cell recruitment
----------------------------------------------------------------------------------------------------------------
Stefanie Dimmeler MOLECULAR CARDIOLOGY, UNIVERSITY OF FRANKFURT
The efficiency of cell therapy to augment recovery after ischemia may be limited by
the rather low recruitment of cells to the target tissue. A new study by Oh and col-
leagues demonstrates that soluble E-selectin increases homing of progenitor cells
by several mechanisms.
ell therapy provides a novel and promising
C option for treatment of ischemic diseases.
However, the homing of infused or injected cells
and safety studies to dramatically reduce the
hemolysis of PNH. Although thrombosis was
not a primary end point of these studies, Hill-
men et al have analyzed the rate of thrombosis
in patients who were taking the drug and com-
pared it with the rate seen while patients were
not taking the drug. There is a dramatic
difference.
The study on thrombosis was not done by
the method that is often considered the gold
standard—the blinded placebo versus the
drug trial. Rather, much of the data for the
“placebo” arm was retrospective, covering a
time period before the drug was given equal to
the time during which the patient was taking
the drug. Nevertheless, the difference is so
great that some systemic bias would be needed
to explain it, which is very unlikely.
Eculizumab will be extensively used in the
treatment of PNH. The careful studies that
are planned will tell whether the incidence of
thrombosis is decreased (as we would expect)
and whether previous or acquired thromboses
can be controlled. From the current data, it
would seem appropriate to use eculizumab in
the treatment and prevention of thrombosis in
selected patients with PNH.
Conflict-of-interest disclosure: The author
declares no competing financial interests. ■
REFERENCES
1. Crosby WH. PNH: relation of the clinical manifesta-
tions to underlying pathogenic mechanisms. Blood. 1953;8:
769-778.
2. Socie G, Mary J-Y, De Gramont A, et al. Paroxysmal
nocturnal haemoglobinuria: long term follow-up and prog-
nostic factors. Lancet. 1996;348:573-577.
3. Nishimura J, Kanakura Y, Ware RE, et al. Clinical
course and flow cytometric analysis of paroxysmal nocturnal
hemoglobinuria in the United States and Japan. Medicine
(Baltimore). 2004;83:193-207.
is limited, with 2% to 10% of the infused cells
being detectable in the target tissue. Strategies to
improve homing and engraftment may provide
3821