Banas, B.

Schiffl, Helmut

Sitter, Thomas

Spannagl, M.

English

Open Access LMU ( Ludwig-Maximilians-Univ. München)

Letter to the EditorNephron 1998;79:245–246Prevalence of Heparin-InducedPF4-Heparin Antibodies inHemodialysis PatientsT. SitterM. SpannaglB. BanasH. SchifflMedizinische Klinik, Klinikum Innenstadt,Universität München, DeutschlandDr. Thomas SitterMedizinische Klinik, Klinikum Innenstadt der Universität MünchenZiemssenstrasse 1D–80336 Munich (Germany)Tel. +49 (89) 5160 2220, Fax +49 (89) 5160 4924ABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com© 1998 S. Karger AG, Basel0028–2766/98/0792–0245$15.00/0This article is also accessible online at:http://BioMedNet.com/kargerDear Sir,Heparin-induced thrombocytopenia(HIT) associated with severe thromboticevents is a well-recognized complication ofheparin therapy. The frequency of HIT var-ies widely in different reports and cumula-tive data suggest a prevalence of about 1–5%in patients treated with unfractionated hepa-rin [1, 2]. In most cases HIT manifests withplatelet counts below 100 ! 103/ml within5–10 days after heparin therapy. An immu-nological mechanism has been emphasizedto be involved in the development of HITand thrombosis [3, 4]. It has been proposedthat heparin complexed to platelet factor 4(PF4) is a target for IgG antibodies. Theimmune complexes generated consist of hep-arin, PF4 and IgG, bind to circulating plate-lets via the Fc receptor and induce a cycle ofplatelet activation and consumption. Para-doxically, thromboembolic complicationsmay develop in some patients with HIT, pos-sibly by in vivo platelet activation [5]. Basedon this hypothesis, an enzyme-linked immu-nosorbent assay (ELISA) was recently devel-oped to detect anti-PF4-heparin antibodiesin the serum of HIT patients [3].The available data on the frequency ofHIT mainly concern patients receiving hepa-rin during a relatively short period of time[2]. Since patients on hemodialysis are re-peatedly exposed to heparin, one might ex-pect a higher frequency of heparin-depen-dent antibodies associated with HIT in thisgroup of patients. In the present study weinvestigated the prevalence of antibodiesagainst PF4-heparin complexes in patientson regular hemodialysis. Patient characteris-tics are outlined in table 1. All patients weretreated 3 times a week with unfractionatedheparin consisting of a single intravenousbolus injection (1,000–5,000 IU) at the be-ginning of each dialysis session followed bycontinuous infusion (1,000–2,000 IU/h) for4–5 h. Blood samples were collected at thebeginning of a hemodialysis session forplatelet counts. IgG antibodies to PF4-hepa-rin complexes were detected by an ELISA asdescribed by Amiral et al. [3]. The results aregiven as the optical density at 492 nm. Usinghealthy subjects (n = 20, OD ! 0.25) and pos-itive standards as controls, an OD 1 0.5 wasconsidered positive.In only 1 of our patients was the plateletcount !100 ! 103/Ìl, but in this patient hep-arin-induced antibodies were not detected.However, anti-PF4-heparin IgG antibodieswere found in 2 patients (OD 0.6 and 1.6)with normal platelet counts. None of the2 patients had thromboembolic complica-tions and no unexpected clot formation indialyzers or extracorporeal circuits was ob-served during an observation period of 6months following the blood sampling. In ourstudy the prevalence of IgG antibodies toPF4-heparin complexes in patients with end-stage renal failure on chronic hemodialysiswas 2.8%. The finding is consistent with aprevious report [6], where the prevalence ofheparin-dependent antibodies in hemodialy-sis patients was 2.3% and the presence ofthese antibodies was also not associated withthe clinical picture of HIT.The prevalence of HIT seems to be high-er at the beginning of hemodialysis treat-ment. In 3.9% (6 of 154) of patients newlytreated with hemodialysis, Yamamoto et al.[7] observed HIT with thromboembolicevents within 60 days after initiation oftreatment, and 5 of 6 patients had positivelevels of anti-PF4-heparin antibodies. Simi-lar observations were made in orthopedicpatients who received low-dose heparin forprophylaxis against deep venous thrombosis[2]. In summary our data demonstrate thathemodialysis patients, who are repeatedlyexposed to heparin over a long period oftime, have a low prevalence of antibodies toPF4-heparin complexes. The clinical rele-vance of these antibodies is as yet unknownbut their presence does not seem to be asso-ciated with the clinical picture of HIT. How-ever, the detection of heparin-dependent an-tibodies seems to be relevant during the firstweeks after initiation of hemodialysis [7, 8].Table 1. Characteristics of hemodialysispatientsNumber of patients 70SexMale/female 41/29Mean age, years (BSD) 54B13Mean duration of hemodialysis,months (BSEM) 75B9Primary renal diseasesChronic glomerulonephritis 22Polycystic kidney disease 11Diabetic nephropathy 10Interstitial nephritis 10Nephrosclerosis 9Others 8246 Nephron 1998;79:245–246 Sitter/Spannagl/Banas/SchifflOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOReferences1 Warkentin TE, Kelton JG: Heparin inducedthrombocytopenia. Prog Hemost Thromb1991;10:1–34.2 Warkentin TE, Levine MN, Hirsch J, Horse-wood P, Roberts RS, Gent M, Kelton JG: Hep-arin induced thrombocytopenia in patientstreated with low-molecular-weight heparin orunfractionated heparin. N Engl J Med 1995;332:1330–1335.3 Amiral J, Bridej F, Dreyfus M, Vissac AM,Fressinaud E, Wolf M, Meyer D: Platelet fac-tor 4 complexed to heparin is the target forantibodies generated in heparin inducedthrombocytopenia. Thromb Haemost 1992;68:95–96.4 Visentin GP, Ford SE, Scott JP, Aster RH:Antibodies from patients with heparin inducedthrombocytopenia/thrombosis are specific forplatelet factor 4 complexed with heparin orbound to endothelial cells. J Clin Invest 1994;93:81–88.5 Warkentin TE, Hayward CPM, Boshkov LK,Santos AV, Sheppard JA, Bode AP, Kelton JG:Sera from patients with heparin inducedthrombocytopenia generate platelet derivedmicroparticles with procoagulant activity: Anexplanation for the thrombotic complicationsof heparin induced thrombocytopenia. Blood1994;84:3691–3699.6 Boon DMS, van Vliet HHDM, Zietse R, Kap-pers-Klunne M: The presence of antibodiesagainst a PF4-heparin complex in patients onhaemodialysis. Thromb Haemost 1996;76:480.7 Yamamoto S, Koide M, Matsuo M, Suzuki S,Ohtaka M, Saika S, Matsuo T: Heparin-in-duced thrombocytopenia in hemodialysis pa-tients. Am J Kidney Dis 1996;28:82–85.8 Finazzi G, Remuzzi G: Heparin-inducedthrombocytopenia: Background and implica-tions for haemodialysis. Nephrol Dial Trans-plant 1996;11:2120–2122.AnnouncementOOOOOOOOOOOOOOOOOOOOOO9th International Congress on Nutrition and Metabolism inRenal DiseaseHofburg Congress Center, Vienna, Austria, August 29–September 1, 1998The scientific program will include the following topics:E Metabolic impact of renal replacement therapy. Exercise and rehabilitation in uremia andafter kidney transplantation. Molecular genetics of lipid metabolism in uremia. Micronu-trients in renal disease. Nitric oxide and arginine metabolism in renal disease. Nephroticsyndrome: metabolism in dietary management. Calcium metabolism and novel vitaminD analogues. Muscle wasting in uremia. Molecular genetics of homocysteine metabolism.Insulin resistance. Growth factors in renal disease. Metabolic impact of acute renalfailure.E 500–600 delegates (international) will participate; the congress language is English (partlywith simultaneous translation).For further information, please contact:Springer-Verlag KG – CongressesSachsenplatz 4–6A–1201 Vienna (Austria)Tel. +43 (1) 330 24 15 238, Fax +43 (1) 330 24 26 260

Aster RH: Antibodies from patients with heparin induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells.

E 500–600 delegates (international) will participate; the congress language is English (partly with simultaneous translation). For further information, please contact:

Heparin induced thrombocytopenia. Prog Hemost Thromb

Heparin-induced thrombocytopenia: Background and implications for haemodialysis. Nephrol Dial Transplant 1996;11:2120–2122. Announcement OOOOOOOOOOOOOOOOOOOOOO 9th International Congress on Nutrition and Metabolism in Renal Disease Hofburg Congress Center,

JG: Heparin induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.

JG: Sera from patients with heparin induced thrombocytopenia generate platelet derived microparticles with procoagulant activity: An explanation for the thrombotic complications of heparin induced thrombocytopenia.

Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin induced thrombocytopenia. Thromb Haemost 1992;68:

T: Heparin-induced thrombocytopenia in hemodialysis patients.

The presence of antibodies against a PF4-heparin complex in patients on haemodialysis. Thromb Haemost 1996;76:

Prevalence of heparin-induced PF4-heparin antibodies in hemodialysis patients

Universität München: Elektronischen Publikationen

Letter to the Editor
Nephron 1998;79:245–246
Prevalence of Heparin-Induced
PF4-Heparin Antibodies in
Hemodialysis Patients
T. Sitter
M. Spannagl
B. Banas
H. Schiffl
Medizinische Klinik, Klinikum Innenstadt,
Universität München, Deutschland
Dr. Thomas Sitter
Medizinische Klinik, Klinikum Innenstadt der Universität München
Ziemssenstrasse 1
D–80336 Munich (Germany)
Tel. +49 (89) 5160 2220, Fax +49 (89) 5160 4924
ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
© 1998 S. Karger AG, Basel
0028–2766/98/0792–0245$15.00/0
This article is also accessible online at:
http://BioMedNet.com/karger
Dear Sir,
Heparin-induced thrombocytopenia
(HIT) associated with severe thrombotic
events is a well-recognized complication of
heparin therapy. The frequency of HIT var-
ies widely in different reports and cumula-
tive data suggest a prevalence of about 1–5%
in patients treated with unfractionated hepa-
rin [1, 2]. In most cases HIT manifests with
platelet counts below 100 ! 103/ml within
5–10 days after heparin therapy. An immu-
nological mechanism has been emphasized
to be involved in the development of HIT
and thrombosis [3, 4]. It has been proposed
that heparin complexed to platelet factor 4
(PF4) is a target for IgG antibodies. The
immune complexes generated consist of hep-
arin, PF4 and IgG, bind to circulating plate-
lets via the Fc receptor and induce a cycle of
platelet activation and consumption. Para-
doxically, thromboembolic complications
may develop in some patients with HIT, pos-
sibly by in vivo platelet activation [5]. Based
on this hypothesis, an enzyme-linked immu-
nosorbent assay (ELISA) was recently devel-
oped to detect anti-PF4-heparin antibodies
in the serum of HIT patients [3].
The available data on the frequency of
HIT mainly concern patients receiving hepa-
rin during a relatively short period of time
[2]. Since patients on hemodialysis are re-
peatedly exposed to heparin, one might ex-
pect a higher frequency of heparin-depen-
dent antibodies associated with HIT in this
group of patients. In the present study we
investigated the prevalence of antibodies
against PF4-heparin complexes in patients
on regular hemodialysis. Patient characteris-
tics are outlined in table 1. All patients were
treated 3 times a week with unfractionated
heparin consisting of a single intravenous
bolus injection (1,000–5,000 IU) at the be-
ginning of each dialysis session followed by
continuous infusion (1,000–2,000 IU/h) for
4–5 h. Blood samples were collected at the
beginning of a hemodialysis session for
platelet counts. IgG antibodies to PF4-hepa-
rin complexes were detected by an ELISA as
described by Amiral et al. [3]. The results are
given as the optical density at 492 nm. Using
healthy subjects (n = 20, OD ! 0.25) and pos-
itive standards as controls, an OD 1 0.5 was
considered positive.
In only 1 of our patients was the platelet
count !100 ! 103/Ìl, but in this patient hep-
arin-induced antibodies were not detected.
However, anti-PF4-heparin IgG antibodies
were found in 2 patients (OD 0.6 and 1.6)
with normal platelet counts. None of the
2 patients had thromboembolic complica-
tions and no unexpected clot formation in
dialyzers or extracorporeal circuits was ob-
served during an observation period of 6
months following the blood sampling. In our
study the prevalence of IgG antibodies to
PF4-heparin complexes in patients with end-
stage renal failure on chronic hemodialysis
was 2.8%. The finding is consistent with a
previous report [6], where the prevalence of
heparin-dependent antibodies in hemodialy-
sis patients was 2.3% and the presence of
these antibodies was also not associated with
the clinical picture of HIT.
The prevalence of HIT seems to be high-
er at the beginning of hemodialysis treat-
ment. In 3.9% (6 of 154) of patients newly
treated with hemodialysis, Yamamoto et al.
[7] observed HIT with thromboembolic
events within 60 days after initiation of
treatment, and 5 of 6 patients had positive
levels of anti-PF4-heparin antibodies. Simi-
lar observations were made in orthopedic
patients who received low-dose heparin for
prophylaxis against deep venous thrombosis
[2]. In summary our data demonstrate that
hemodialysis patients, who are repeatedly
exposed to heparin over a long period of
time, have a low prevalence of antibodies to
PF4-heparin complexes. The clinical rele-
vance of these antibodies is as yet unknown
but their presence does not seem to be asso-
ciated with the clinical picture of HIT. How-
ever, the detection of heparin-dependent an-
tibodies seems to be relevant during the first
weeks after initiation of hemodialysis [7, 8].
Table 1. Characteristics of hemodialysis
patients
Number of patients 70
Sex
Male/female 41/29
Mean age, years (BSD) 54B13
Mean duration of hemodialysis,
months (BSEM) 75B9
Primary renal diseases
Chronic glomerulonephritis 22
Polycystic kidney disease 11
Diabetic nephropathy 10
Interstitial nephritis 10
Nephrosclerosis 9
Others 8
246 Nephron 1998;79:245–246 Sitter/Spannagl/Banas/Schiffl
OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO
References
1 Warkentin TE, Kelton JG: Heparin induced
thrombocytopenia. Prog Hemost Thromb
1991;10:1–34.
2 Warkentin TE, Levine MN, Hirsch J, Horse-
wood P, Roberts RS, Gent M, Kelton JG: Hep-
arin induced thrombocytopenia in patients
treated with low-molecular-weight heparin or
unfractionated heparin. N Engl J Med 1995;
332:1330–1335.
3 Amiral J, Bridej F, Dreyfus M, Vissac AM,
Fressinaud E, Wolf M, Meyer D: Platelet fac-
tor 4 complexed to heparin is the target for
antibodies generated in heparin induced
thrombocytopenia. Thromb Haemost 1992;68:
95–96.
4 Visentin GP, Ford SE, Scott JP, Aster RH:
Antibodies from patients with heparin induced
thrombocytopenia/thrombosis are specific for
platelet factor 4 complexed with heparin or
bound to endothelial cells. J Clin Invest 1994;
93:81–88.
5 Warkentin TE, Hayward CPM, Boshkov LK,
Santos AV, Sheppard JA, Bode AP, Kelton JG:
Sera from patients with heparin induced
thrombocytopenia generate platelet derived
microparticles with procoagulant activity: An
explanation for the thrombotic complications
of heparin induced thrombocytopenia. Blood
1994;84:3691–3699.
6 Boon DMS, van Vliet HHDM, Zietse R, Kap-
pers-Klunne M: The presence of antibodies
against a PF4-heparin complex in patients on
haemodialysis. Thromb Haemost 1996;76:
480.
7 Yamamoto S, Koide M, Matsuo M, Suzuki S,
Ohtaka M, Saika S, Matsuo T: Heparin-in-
duced thrombocytopenia in hemodialysis pa-
tients. Am J Kidney Dis 1996;28:82–85.
8 Finazzi G, Remuzzi G: Heparin-induced
thrombocytopenia: Background and implica-
tions for haemodialysis. Nephrol Dial Trans-
plant 1996;11:2120–2122.
Announcement
OOOOOOOOOOOOOOOOOOOOOO
9th International Congress on Nutrition and Metabolism in
Renal Disease
Hofburg Congress Center, Vienna, Austria, August 29–September 1, 1998
The scientific program will include the following topics:
E Metabolic impact of renal replacement therapy. Exercise and rehabilitation in uremia and
after kidney transplantation. Molecular genetics of lipid metabolism in uremia. Micronu-
trients in renal disease. Nitric oxide and arginine metabolism in renal disease. Nephrotic
syndrome: metabolism in dietary management. Calcium metabolism and novel vitamin
D analogues. Muscle wasting in uremia. Molecular genetics of homocysteine metabolism.
Insulin resistance. Growth factors in renal disease. Metabolic impact of acute renal
failure.
E 500–600 delegates (international) will participate; the congress language is English (partly
with simultaneous translation).
For further information, please contact:
Springer-Verlag KG – Congresses
Sachsenplatz 4–6
A–1201 Vienna (Austria)
Tel. +43 (1) 330 24 15 238, Fax +43 (1) 330 24 26 260


Sitter, T.

Schiffl, H.

University of Regensburg Publication Server

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Prevalence of heparin-induced PF4-heparin antibodies in hemodialysis patients

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