- Email: [email protected]
Tolerance of Fondaparinux in Immediate-type Hypersensitivity to Heparins
Accepted Manuscript Tolerance of fondaparinux in immediate type hypersensitivity to heparins Luisa M. Trog, MD, Birgit Kahle, MD, Marc Schindewolf, MD, Uta Jappe, MD, Ralf J. Ludwig, MD PII:
S0002-9343(15)00575-6
DOI:
10.1016/j.amjmed.2015.06.024
Reference:
AJM 13074
To appear in:
The American Journal of Medicine
Received Date: 8 May 2015 Revised Date:
18 June 2015
Accepted Date: 22 June 2015
Please cite this article as: Trog LM, Kahle B, Schindewolf M, Jappe U, Ludwig RJ, Tolerance of fondaparinux in immediate type hypersensitivity to heparins, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2015.06.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Tolerance of fondaparinux in immediate type hypersensitivity to heparins
Luisa M. Trog, MD1, Birgit Kahle, MD1, Marc Schindewolf, MD2, Uta Jappe, MD1,3 and Ralf J.
RI PT
Ludwig, MD1,4
1
Department of Dermatology, University of Lübeck, Germany; 2Swiss Cardiovascular Center,
Division of Vascular Medicine, University Hospital Bern, Bern, Switzerland; 3Division of
SC
Clinical and Molecular Allergology, Research Center Borstel, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany; 4
M AN U
Lübeck Institute of Experimental Dermatology, University of Lübeck, Germany
Funding sources: None
TE D
Conflict of interest: None
Article type: Clinical Communications to the Editor Key words: Heparin, fondaparinux, allergy, immediate type hypersensitivity
EP
Running head: Tolerance of fondaparinux in immediate type hypersensitivity to heparins
AC C
Verification: All authors had access to the data and a role in writing the manuscript.
Corresponding author: Ralf J. Ludwig, MD
Lübeck Institute of Experimental Dermatology, University of Lübeck, Ratzeburger Allee 160,
D-23538 Lübeck, Germany; Phone: +49 451 500-2541; Fax: +49 451 500-5162; E-mail: [email protected]
1
ACCEPTED MANUSCRIPT
Case Report To the Editor, subcutaneously administered anticoagulants, including unfractionated heparin (UFH), low-molecular-weight heparins (LMWH), semisynthetic heparinoids, and the synthetic
RI PT
pentasaccharide fondaparinux, are used for treatment and prophylaxis of thromboembolic disorders. Delayed-type hypersensitivity reactions are common adverse events of s.c. heparin1. Contrary, immediate-type hypersensitivity reactions to heparins are rare1. Clinical
SC
manifestations of immediate hypersensitivity to heparins range from local wheals to anaphylaxis2,3. Based on single case-reports, (i) switch to a chemically different
M AN U
anticoagulant3 or heparinoids4, (ii) specific immunotherapy5, or (iii) switch to the synthetic pentasaccharide fondaparinux2, have been reported as alternatives for immediate hypersensitivity to heparins. Yet, this is based on mostly single observations, and thus very little expertise (beyond acute care) for treatment of immediate hypersensitivity to heparins is
TE D
available.
We report a 47-year-old female Caucasian patient who underwent endoluminal lasercoagulation of the right great saphenous vein for chronic venous insufficiency. LMWH
EP
tinzaparin was prescribed to prevent deep vein thrombosis. The patient took no other concomitant drugs. Thirty minutes after the third tinzaparin injection (1x3,500 IU/day), the
AC C
patient experienced dizziness, nausea and headaches. Tinzaparin was discontinued, and symptoms resolved. The patient was referred to our allergy department for testing. A skinprick test (SPT) with tinzaparin, danaparoid and fondaparinux was performed. We refrained from including UFH and other LWMH, as (albeit based on few reports) a high grade of cross-reactivity has been documented2-4. Approximately 10 minutes after start of the SPT, she complained of dizziness. At this time point, reading for negative control (saline) was negative, while positive control (histamine) had induced a wheal and erythema. Response to tinzaparin and danaparoid were comparable to histamine, while SPT with fondaparinux was negative at this (and later) time point. The patient’s history and SPT results led to the 2
ACCEPTED MANUSCRIPT diagnosis of an immediate reaction to tinzaparin and danaparoid. To confirm the negative SPT result for fondaparinux, an alternative anticoagulant that can be used for treatment of myocardial infarction and pulmonary embolism, the patient underwent a challenge test with fondaparinux, which was administered subcutaneously at increasing doses starting from
RI PT
0.025 to 2.5 mg. The latter, at a cumulative dose of 3.84 mg, was well tolerated by the patient.
Collectively, we describe the second patient with immediate hypersensitivity to heparins and
SC
heparinoids that tolerated fondaparinux, which, should be considered as a potential alternative for patients with immediate hypersensitivity to heparins. Compared to the other
M AN U
described alternative (see above), fondaparinux is an alternative that, given tolerance has been shown in prick testing, can be used readily and is licensed for emergency situations, i.e. pulmonary embolism6. Before use of any heparin-based alternative anticoagulant, prick testing is required. Testing should include fondaparinux, as positive prick tests for this
tolerated
in
TE D
anticoagulant have been reported3. Switching to intravenously heparin (UFH), which is delayed-type
is
not
an
option
for
immediate-type
AC C
EP
hypersensitivity.
hypersensitivity1,
3
ACCEPTED MANUSCRIPT
References 1.
Schindewolf, M., E. Lindhoff-Last, R. J. Ludwig, and W. H. Boehncke. 2012. Heparininduced skin lesions. Lancet 380: 1867-1879.
2.
Harr, T., K. Scherer, D. A. Tsakiris, and A. J. Bircher. 2006. Immediate type
and fondaparinux. Allergy 61: 787-788.
Anders, D., and A. Trautmann. 2013. Allergic anaphylaxis due to subcutaneously injected heparin. Allergy Asthma Clin Immunol 9: 1.
4.
Berkun, Y., Y. S. Haviv, L. B. Schwartz, and M. Shalit. 2004. Heparin-induced recurrent anaphylaxis. Clin Exp Allergy 34: 1916-1918.
5.
Dave, S., and M. A. Park. 2008. Successful heparin desensitization: a case report and review of the literature. J Card Surg 23: 394-397.
M AN U
Büller, H. R., B. L. Davidson, H. Decousus, A. Gallus, M. Gent, F. Piovella, M. H. Prins, G. Raskob, A. E. van den Berg-Segers, R. Cariou, O. Leeuwenkamp, A. W. Lensing, and Matisse, Investigators. 2003. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 349:
EP
TE D
1695-1702.
AC C
6.
SC
3.
RI PT
hypersensitivity to low molecular weight heparins and tolerance of unfractioned heparin
4
S0002-9343(15)00575-6
DOI:
10.1016/j.amjmed.2015.06.024
Reference:
AJM 13074
To appear in:
The American Journal of Medicine
Received Date: 8 May 2015 Revised Date:
18 June 2015
Accepted Date: 22 June 2015
Please cite this article as: Trog LM, Kahle B, Schindewolf M, Jappe U, Ludwig RJ, Tolerance of fondaparinux in immediate type hypersensitivity to heparins, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2015.06.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Tolerance of fondaparinux in immediate type hypersensitivity to heparins
Luisa M. Trog, MD1, Birgit Kahle, MD1, Marc Schindewolf, MD2, Uta Jappe, MD1,3 and Ralf J.
RI PT
Ludwig, MD1,4
1
Department of Dermatology, University of Lübeck, Germany; 2Swiss Cardiovascular Center,
Division of Vascular Medicine, University Hospital Bern, Bern, Switzerland; 3Division of
SC
Clinical and Molecular Allergology, Research Center Borstel, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany; 4
M AN U
Lübeck Institute of Experimental Dermatology, University of Lübeck, Germany
Funding sources: None
TE D
Conflict of interest: None
Article type: Clinical Communications to the Editor Key words: Heparin, fondaparinux, allergy, immediate type hypersensitivity
EP
Running head: Tolerance of fondaparinux in immediate type hypersensitivity to heparins
AC C
Verification: All authors had access to the data and a role in writing the manuscript.
Corresponding author: Ralf J. Ludwig, MD
Lübeck Institute of Experimental Dermatology, University of Lübeck, Ratzeburger Allee 160,
D-23538 Lübeck, Germany; Phone: +49 451 500-2541; Fax: +49 451 500-5162; E-mail: [email protected]
1
ACCEPTED MANUSCRIPT
Case Report To the Editor, subcutaneously administered anticoagulants, including unfractionated heparin (UFH), low-molecular-weight heparins (LMWH), semisynthetic heparinoids, and the synthetic
RI PT
pentasaccharide fondaparinux, are used for treatment and prophylaxis of thromboembolic disorders. Delayed-type hypersensitivity reactions are common adverse events of s.c. heparin1. Contrary, immediate-type hypersensitivity reactions to heparins are rare1. Clinical
SC
manifestations of immediate hypersensitivity to heparins range from local wheals to anaphylaxis2,3. Based on single case-reports, (i) switch to a chemically different
M AN U
anticoagulant3 or heparinoids4, (ii) specific immunotherapy5, or (iii) switch to the synthetic pentasaccharide fondaparinux2, have been reported as alternatives for immediate hypersensitivity to heparins. Yet, this is based on mostly single observations, and thus very little expertise (beyond acute care) for treatment of immediate hypersensitivity to heparins is
TE D
available.
We report a 47-year-old female Caucasian patient who underwent endoluminal lasercoagulation of the right great saphenous vein for chronic venous insufficiency. LMWH
EP
tinzaparin was prescribed to prevent deep vein thrombosis. The patient took no other concomitant drugs. Thirty minutes after the third tinzaparin injection (1x3,500 IU/day), the
AC C
patient experienced dizziness, nausea and headaches. Tinzaparin was discontinued, and symptoms resolved. The patient was referred to our allergy department for testing. A skinprick test (SPT) with tinzaparin, danaparoid and fondaparinux was performed. We refrained from including UFH and other LWMH, as (albeit based on few reports) a high grade of cross-reactivity has been documented2-4. Approximately 10 minutes after start of the SPT, she complained of dizziness. At this time point, reading for negative control (saline) was negative, while positive control (histamine) had induced a wheal and erythema. Response to tinzaparin and danaparoid were comparable to histamine, while SPT with fondaparinux was negative at this (and later) time point. The patient’s history and SPT results led to the 2
ACCEPTED MANUSCRIPT diagnosis of an immediate reaction to tinzaparin and danaparoid. To confirm the negative SPT result for fondaparinux, an alternative anticoagulant that can be used for treatment of myocardial infarction and pulmonary embolism, the patient underwent a challenge test with fondaparinux, which was administered subcutaneously at increasing doses starting from
RI PT
0.025 to 2.5 mg. The latter, at a cumulative dose of 3.84 mg, was well tolerated by the patient.
Collectively, we describe the second patient with immediate hypersensitivity to heparins and
SC
heparinoids that tolerated fondaparinux, which, should be considered as a potential alternative for patients with immediate hypersensitivity to heparins. Compared to the other
M AN U
described alternative (see above), fondaparinux is an alternative that, given tolerance has been shown in prick testing, can be used readily and is licensed for emergency situations, i.e. pulmonary embolism6. Before use of any heparin-based alternative anticoagulant, prick testing is required. Testing should include fondaparinux, as positive prick tests for this
tolerated
in
TE D
anticoagulant have been reported3. Switching to intravenously heparin (UFH), which is delayed-type
is
not
an
option
for
immediate-type
AC C
EP
hypersensitivity.
hypersensitivity1,
3
ACCEPTED MANUSCRIPT
References 1.
Schindewolf, M., E. Lindhoff-Last, R. J. Ludwig, and W. H. Boehncke. 2012. Heparininduced skin lesions. Lancet 380: 1867-1879.
2.
Harr, T., K. Scherer, D. A. Tsakiris, and A. J. Bircher. 2006. Immediate type
and fondaparinux. Allergy 61: 787-788.
Anders, D., and A. Trautmann. 2013. Allergic anaphylaxis due to subcutaneously injected heparin. Allergy Asthma Clin Immunol 9: 1.
4.
Berkun, Y., Y. S. Haviv, L. B. Schwartz, and M. Shalit. 2004. Heparin-induced recurrent anaphylaxis. Clin Exp Allergy 34: 1916-1918.
5.
Dave, S., and M. A. Park. 2008. Successful heparin desensitization: a case report and review of the literature. J Card Surg 23: 394-397.
M AN U
Büller, H. R., B. L. Davidson, H. Decousus, A. Gallus, M. Gent, F. Piovella, M. H. Prins, G. Raskob, A. E. van den Berg-Segers, R. Cariou, O. Leeuwenkamp, A. W. Lensing, and Matisse, Investigators. 2003. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 349:
EP
TE D
1695-1702.
AC C
6.
SC
3.
RI PT
hypersensitivity to low molecular weight heparins and tolerance of unfractioned heparin
4