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Increased levels of total and free protein S in hemophiliacs irrespective of human immunodeficiency virus type-1 infection.

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Letters and Correspondence
I . Alter HJ, Purcell RH, Shih JW, Melpolder JC, Houghton M, Choo QL, Kuo G:
Detection of antibody to hepatitis C virus in prospectively followed transfusion
recipients wlth acute and chronic non-A. non-B hepatitis. N Engl J Med 321:49&
500, 1989.
2. Donahue JG, Munoz A, Ness PM, Brown DE, Yawn DH, McAllister HA, Reitz
BA, Nelson KE: The declining risk of post-transfusion hepatitis C virus infection.
N Engl J Med 321:369-13. 1992.
3. Seeff LB, Buskell-Bales 2, Wright EC, et al.: Long-term mortality after transfusion associated non-A, non-B hepatitis. N Engl J Med 327:190&11, 1993.
4. Johnson RJ, Gretch DR, Yamabe H, et al.: Membranoproliferativeglomerulonephritis associated with hepatitis C virus infection. N Engl J Med 328:465-70,
Increased Levels of Total and Free Protein S in
Hemophiliacs Irrespective of Human Immunodeficiency
Virus Type-1 Infection
To the Editor: Abnormally high or low levels of protein S may reflect the
presence of functional abnormality and/or injury of the endothelium related
to human immunodeficiently virus type-I (HIV-1) infection [1,2]. However, to our knowledge, there have been no investigations of plasma protein
S, including tissue plasminogen activator (tPA), endothelin-1 (ET-I),
thrombomodulin (TM), and C4-binding protein (C4bp) in hemophiliacs
infected with HIV-1. Accordingly, we conducted this study to clarify
whether or not total and free protein S was increased or decreased in
hemophiliacs with HIV-1 infection. We studied 41 hemophiliacs including
24 who were positive for HIV-I antibody (all asymptomatic camers).
Protein S (total and free) and tPA were measured using the Asserachrom
Protein S kit (Stago, France) and Imulyse Tm tPA Kit (Biopool, Sweden),
respectively. ET-I, TM, and C4bp were measured using an ET-I test kit
(Takeda Chemical, Japan), TM test kit (Mitsubishi Gas, Japan), and C4bp
test kit (Fuji Yakuhin, Japan), respectively.
The mean total protein S level was higher in both HIV-I positive hemophiliacs (200 ? 76%) (P < 0.01) (Student t-test) and HIV-I negative hemophiliacs (256 ? 89%) (P < 0.01) than in the controls (88 ? 5%) (Fig.
1). Mean free protein S levels were also higher in the HIV-1 positive
hemophiliacs (88 -+ 25%) (P< 0.01) and HIV-I negative hemopiliacs
(1 17 % 41%) (P < 0.01) than in the controls (63 t 23%). Both the mean
total and free protein S levels were higher in the HIV-I negative hemophiliacs than in those positive for HIV-1 infection (P < 0.05 and P < 0.01,
respectively). There were no significant differences in C4bp, TM, tPA, and
ET-I levels between the hemophiliacs with or without HIV-I infection and
the controls.
Lafeuillade et al. [I] have reported that the plasma protein S level was
significantly reduced in patients with HIV-I infection. In contrast, our
hemophiliacs had significantly higher levels of total and free protein S .
Protein S is known to increase in patients with active inflammation, and to
decrease in patients with liver damage [2] and in patients with anticardiolipin antibody (aCL)/lupus anticoagulant (LA) [ 3 ] .However, our patients
3 200
q tj
Healthy HIV-negative HIV-positive
HIV-nemtive HIV-positive
Fig. 1. The plasma levels of total and free protein S in hemophiliacs with or without human immunodeficiency virus type-1 (HIV-1) infection. 0,
hemophilia A; 0,hemophilia 8 ; **, P < 0.01; *, P < 0.05.
Letters and Correspondence
response may be expected by a prolonged administration of G-CSF in such
patients. Our recent experience may illustrate an example of long-term
administration of G-CSF to a patient with severe aplastic anemia with
ultimate response of granulocytes.
An 18-year-old male was diagnosed as having idiopathic aplastic anemia
in January 1991. His white blood cell count was 1,3OO/plwith 5% granulocytes, platelet count was 3,OOO/p1, no reticulocytes were found. He did
not respond to oral prednisolone, subcutaneous granulocyte-macrophage
colony-stimulating factor, methylprednisolone pulse therapy, intramuscular testosterone enanthate, subcutaneous G-CSF, or cyclosporin A. A
matched donor for bone marrow transplantation was not available, and
recurrent bacterial infections and sepsis discouraged other immunosuppressive therapies. G-CSF was resumed by daily intravenous drip of 600 pg
(400 pg/m2) over 3 hr on November 1 , 1991, without immediate response.
Granulocytes started to rise in July 1992 and exceeded IO,OOO/plin September, 10 months after the initiation of G-CSF. Subsequently his refractory bacterial infections and recurrent sepsis resolved. Bone marrow aspirate revealed that 80% of the nucleated cells were of myeloid series. In
September, antilymphocyte globulin (ALG) was given. On reduction of
G-CSF, his granulocytes concomitantly declined. However, they increased
again with increment of G-CSF dose. The reticulocytes started to rise in
December 1992, reaching 10O,OOO/pl.Erythroid series accounted for 11%
of the bone marrow nucleated cells. Both granulocytes and reticulocytes
Juzo MATSUDAdeclined following dose-reduction of G-CSF, and increased again with the
increased dose. He is currently in a stable condition although still depenMIYOTSUKAMOTO
GOTOH dent on occasional red cell and regular platelet support. His platelet requireKENGO
GOHCHI ment did not change throughout the course. There were no untoward effects
SAITOH attributable to the prolonged use of G-CSF.
YUKARIMIYAJIMA In the clinical trials on adult aplastic anemia patients, all responders
KAZAMA showed increase of granulocytes within 2 months of G-CSF administration
[2,3]. As for children receiving G-CSF daily for up to 8 weeks, all respondDepartment of Medicine, Teikyo University School of Medicine,
ers showed granulocyte response within 5 weeks [l]. Our case demonItabashi-Ku, Tokyo, Japan
strated a remarkable granulocyte response as late as 10 months after initiation of therapy. The observed response may have been a consequence of
any one or a combination of previous treatments. However, it is likely that
the response was primarily due to G-CSF, since granulocytes fluctuated in a
dose-dependent manner to G-CSF.
1. Lafeuillade A, Alessi MC, Poizot-Martin I, Boyer-Neumann C, Zandotti C, QiliAnother point of interest in our case is the increase in reticulocytes which
chini R, Aubert L, Tamalet C, Juhan-Vague I, Gastaut JA: Endothelial cell dysbecame apparent 4 months behind the change of granulocytes and subsefunction in HIV infection. J Acquire Immuno Defic Syndr 5:127, 1992.
quent decrease following dose reduction of G-CSF, indicating that red cell
2. Walker FJ: Protein S and the regulation of activated protein C. Semin Thromb
production was somehow stimulated by G-CSF [3,4].
were negative for C-reactive protein (CRP) and had normal C4bp levels,
indicating the absence of inflammatory disease. In addition, 95% of the
hemophiliacs were positive for hepatitis C virus antibody, and had slight to
mild liver damage and nearly 80% had aCL [4,5].
Thus, the increment of
protein S in our patients remains unexplained by the above-mentioned
factors, and it may in fact reflect endothelial stimulation and/or injury.
It seems possible that HIV-I may bind to endothelial cells [ l ] and
stimulate them to release these factors, with repetition of this process
eventually causing endothelial injury andlor dysfunction. It is interesting
that total and free protein S levels were higher in HIV-I-negative hemophiliacs than in those with HIV-1 infection. This suggests that a possible cause
of the increase in protein S may be stimulation of the endothelium by
certain agents, other than HIV-I, such as cytokines. However, the ET-1
and tPA concentrations were essentially normal in hemophilia patients
irrespective of their HIV-I infection status, suggesting that these factors
may be released by different mechanisms.
Repeated infusion of anti-hemophilic factor concentrate which contains
various ailoantigens could cause non-specific activation of the immune
system, and may stimulate the anti-idiotype/idiotype network to produce
cytokines [6] and thus promote release of protein S from the endothelium.
However, the clinical significance of the elevation of protein S levels in
hemophiliacs is not clear at present, and further investigation is needed.
Hemost 10131, 1984.
3. Rossi E, Gatti L, Guameri D, Finotto E, Lombardi A, Preda L Functional protein
S in women with lupus anticoagulant inhibitor. Thromb Res 65:253, 1992.
4. Matsuda J , Saitoh N , Tsukamoto M, Gohchi K, Asami K, Hashimoto, N: Measurement of P2-glycoprotein I (apolipoprotein-H) independent anticardiolipin antibody in human immunodeficiency virus-1-positive and -negative hemophiliacs.
Am J Hematol43:146, 1993.
5. Matsuda I, Gohchi K, Hama H, Tsukamoto M, Saitoh N, Kinoshita T High
prevalence of anticardiolipin antibody Ciq-, C3d-, and mRF-IgG immune complexes, and antinuclear antibody in hemophlilicas irrespective of infection with
human immunodeficiency virus type 1. J Acquir Immuno Defic Syndr 6:1120,
6. Cuthbert RJG, Ludlam CA, Steel CM, Beatson D, Peutherer J F Immunological
studies in HIV seronegative haemophiliacs; relationships to blood product therapy.
Br J Haematol80:364. 1992.
Delayed Granulocyte Response to G-CSF in Aplastic Anemia
To the Editor: Granulocyte colony-stimulating factor (G-CSF) has been
used as an adjuvant therapy for aplastic anemia with improvement in the
granulocyte counts and clearance of infections in some patients [I-31.
However, experience is still limited as to whether delayed granulocyte
Division of Hematology, Showa University Fujigaoka Hospital,
Yokohama, Japan
1. Kojima S, Fukuda M, Miyajima Y, Matsuama T, Horibe K: Treatment of aplastic
anemia in children with recombinant human granulocyte colony-stimulating factor. Blood 77:937, 1991.
2. Bessho M, Toyoda A, Itoh Y, Sakata T. Kawai N, Jinnai I, Saito M, Hirashima K:
Trilineagc recovery by combination therapy with recombinant human granulocyte
colony-stimulating factor (rhG-CSF) and erythropoietin (rhEpo) in severe aplastic
anemia. Br J HaematolSO409, 1992.
3. Sonoda Y, Yashige H, Fujii H, Tsuda S, Maekawa T, Misawa S, Abe T: Bilineage
response in refractory aplastic anemia patients following long-term administration
of recombinant human granulocyte colony-stimulating factor. Eur J Haematol
48:41, 1992.
4. Souza LM, Boone TC, Gabrilove J, Lai GP, Zsebo KM, Murdock DC, Chazin
VR, Bruszewski J, Lu H, Chen KK, Barendt J , Platzer E, Moore MAS, Mertels-
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