PDF herunterladen
Thromb Haemost 2006; 96(05): 611-617
DOI: 10.1160/TH06-04-0210
Review Article
Schattauer GmbH

Management of cutaneous type IV hypersensitivity reactions induced by heparin

Ralf J. Ludwig
1   Department of Dermatology, Clinic of the J.W. Goethe University, Frankfurt am Main, Germany
2   pharmazentrum frankfurt / ZAFES, Clinic of the J.W. Goethe University, Frankfurt am Main, Germany
,
Marc Schindewolf
3   Department of Internal Medicine (Division of Vascular Medicine), Clinic of the J.W. Goethe University, Frankfurt am Main, Germany
,
Jochen Utikal
4   Department of Dermatology, Venerology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University Heidelberg, Mannheim, Germany
,
Edelgard Lindhoff-Last
3   Department of Internal Medicine (Division of Vascular Medicine), Clinic of the J.W. Goethe University, Frankfurt am Main, Germany
,
Wolf-Henning Boehncke
1   Department of Dermatology, Clinic of the J.W. Goethe University, Frankfurt am Main, Germany
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 14. April 2006

Accepted after resubmission 06. September 2006

Publikationsdatum:
01. Dezember 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

Localized hypersensitivity reactions to subcutaneous heparin injections have been described since 1952. Yet, the incidence of these reactions, which are distinct from skin lesions associated with heparin-induced thrombocytopenia type II (HIT II), remains uncertain. However, in the last 10 years an increasing number of patients have been reported, leading to the assumption that cutaneous hypersensitivity reactions towards heparin are underreported. Clinically patients present with itching, sometimes infiltrated, and blistering erythemas at the injection sites of heparins. The diagnosis of cutaneous heparin allergy may, on the one hand, lead to delay of required medical or surgical treatment. On the other hand, delayed initiation of treatment may lead to a generalized eczematous reaction. Hence, from review of 223 cases of patients with cutaneous hypersensitivity reactions to heparin, we here summarize the clinical picture of cutaneous type IV allergic reactions, define risk factors on both the patient- and drug-side, and give an overview of principle therapeutic alternatives, as well as recommendations for treatment options for emergency and elective patients. As the proposed management of patients with cutaneous hypersensitivity reactions to heparin may have fatal consequences when applied in patients with HIT type II, diagnosis of skin lesions in heparin-treated patients needs to be precise.

Keywords

Heparin - inflammation - pharmacology - allergy

Footnotes:

1 In this manuscript the term “heparin” refers to both unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH).


2 Only those publications which clearly documented sensitization towards heparin by prick- patch- or i.e. in-vivo tests, or histological verification of CHS were included. Those, merely describing “skin lesions” after heparin administration or reporting “skin lesions” in the setting of immune heparin-induced thrombocytopenia were excluded from the analysis.


 

  • References

  • 1 Alban S. From heparins to factor Xa inhibitors and beyond. Eur J Clin Invest 2005; 35 (Suppl. 01) 12-20.
    CrossrefPubMedSuche in Google Scholar
  • 2 Lane DA. Heparin binding and neutralizing proteins. In: Heparin. London: Edward Arnold; 1989: 363-91.
    Suche in Google Scholar
  • 3 Alban S, Greinacher A. Role of sulfated polysaccharides in the pathogenesis Marcel Dekker. 2004: 197-221.
    Suche in Google Scholar
  • 4 Plancherel P. Klinische und gerinnungsphysiol-ogische Untersuchungen mit einem neuem Heparinde-potpraparat. Z Klin Med 1952; 150: 213-59.
    PubMedSuche in Google Scholar
  • 5 Ludwig RJ, Schindewolf M, Alban S. et al. Molecular weight determines the frequency of delayed type hypersensitivity reactions to heparin and synthetic oligosaccharides. Thromb Haemost 2005; 94: 1265-9.
    Thieme ConnectPubMedSuche in Google Scholar
  • 6 Grassegger A, Fritsch P, Reider N. Delayed-type hypersensitivity and cross-reactivity to heparins and danaparoid: a prospective study. Dermatol Surg 2001; 27: 47-52.
    PubMedSuche in Google Scholar
  • 7 Utikal J, Peitsch WK, Booken D. et al. Hypersensitivity to the pentasaccharide fondaparinux in patients with delayed-type heparin allergy. Thromb Haemost 2005; 94: 895-6.
    Thieme ConnectPubMedSuche in Google Scholar
  • 8 Klein GF, Kofler H, Wolf H. et al. Eczema-like, erythematous, infiltrated plaques: a common side effect of subcutaneous heparin therapy. J Am Acad Dermatol 1989; 21: 703-7.
    CrossrefPubMedSuche in Google Scholar
  • 9 Bircher AJ. Allergische Reaktionen vom Spattyp auf Heparine. Allergologie 1993; 16: 268-74.
    PubMedSuche in Google Scholar
  • 10 Hirsch K, Ludwig RJ, Lindhoff-Last E. et al. Intolerance of fondaparinux in a patient allergic to heparins. Contact Dermatitis 2004; 06: 383-1.
    PubMedSuche in Google Scholar
  • 11 Jappe U, Juschka U, Kuner N. etal Fondaparinux: a suitable alternative in cases of delayed-type allergy to heparins and semisynthetic heparinoids? A study of 7 cases. Contact Dermatitis 2004; 51: 67-72.
    CrossrefPubMedSuche in Google Scholar
  • 12 Koch P, Munssinger T, Rupp-John C. etal Delayed-type hypersensitivity skin reactions caused by subcutaneous unfractionated and low-molecular-weight heparins: tolerance of a new recombinant hirudin. J Am Acad Dermatol 2000; 42: 612-9.
    CrossrefPubMedSuche in Google Scholar
  • 13 Greiner D, Schofer H. Allergic drug exanthema to heparin. Cutaneous reactions to high molecular and fractionated heparin. Hautarzt 1994; 45: 569-72.
    CrossrefPubMedSuche in Google Scholar
  • 14 Figarella I, Barbaud A, Lecompte T. et al. Cutaneous delayed hypersensitivity reactions to heparins and heparinoids. Ann Dermatol Venereol 2001; 128: 25-30.
    PubMedSuche in Google Scholar
  • 15 Patrizi A, ADi LV, Patrone P. Generalized reaction to subcutaneous heparin. Contact Dermatitis 1989; 20: 309-10.
    CrossrefPubMedSuche in Google Scholar
  • 16 Harenberg J, Hoffmann U, Huhle G. et al. Cutaneous reactions to anticoagulants. Recognition and management. Am J Clin Dermatol 2001; 02: 69-75.
    CrossrefPubMedSuche in Google Scholar
  • 17 Mora A, Belchi J, Contreras L, Rubio G. Delayed-type hypersensitivity skin reactions to low molecular weight heparins in a pregnant woman. Contact Dermatitis 2002; 47: 177-8.
    CrossrefPubMedSuche in Google Scholar
  • 18 Erdmann S, Hertl M, Merk HF. Spattypreaktionen auf Heparine und Heparinoide - Hirudin als therapeu-tische Alternative. Z Hautkrank 1998; 7/8: 505-10.
    PubMedSuche in Google Scholar
  • 19 Tosti A, De Padova MP, Patrizi A. et al. Unusual reaction to subcutaneous heparin. Contact Dermatitis 1985; 13: 190.
    CrossrefPubMedSuche in Google Scholar
  • 20 Koch P, Bahmer FA, Schafer H. Tolerance of intravenous low-molecular-weight heparin after eczema-tous reaction to subcutaneous heparin. Contact Dermatitis 1991; 25: 205-6.
    CrossrefPubMedSuche in Google Scholar
  • 21 Koch P, Hindi S, Landwehr D. Delayed allergic skin reactions due to subcutaneous heparin-calcium, enox-aparin-sodium, pentosan polysulfate and acute skin lesions from systemic sodium-heparin. Contact Dermatitis 1996; 34: 156-8.
    CrossrefPubMedSuche in Google Scholar
  • 22 Boehncke WH, Weber L, Gall H. Tolerance to intravenous administration of heparin and heparinoid in a patient with delayed-type hypersensitivity to heparins and heparinoids. Contact Dermatitis 1996; 35: 73-5.
    CrossrefPubMedSuche in Google Scholar
  • 23 Mendez J, Sanchis ME, de la FR. et al. Delayed-type hypersensitivity to subcutaneous enoxaparin. Allergy 1998; 53: 999-1003.
    CrossrefPubMedSuche in Google Scholar
  • 24 Bircher AJ, Itin PH, Tsakiris DA. et al. Delayed hypersensitivity to one low-molecular-weight heparin with tolerance of other low-molecular-weight heparins. Br J Dermatol 1995; 132: 461-3.
    CrossrefPubMedSuche in Google Scholar
  • 25 Warkentin TE, Sheppard JA, Sigouin CS. et al. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood. 2006 Epub ahead of print (PMID: 16857993).
    PubMedSuche in Google Scholar
  • 26 Bircher AJ, Fluckiger R, Buchner SA. Eczematous infiltrated plaques to subcutaneous heparin: a type TV allergic reaction. Br J Dermatol 1990; 123: 507-14.
    PubMedSuche in Google Scholar
  • 27 Ludwig RJ, Beier C, Lindhoff-Last E. et al. Tolerance of fondaparinux in a patient allergic to heparins and other glycosaminoglycans. Contact Dermatitis 2003; 49: 158-9.
    CrossrefPubMedSuche in Google Scholar
  • 28 Moreau A, Dompmartin A, Esnault P. et al. Delayed hypersensitivity at the injection sites of a low-molecular-weight heparin. Contact Dermatitis 1996; 34: 31-04.
    CrossrefPubMedSuche in Google Scholar
  • 29 Szolar-Platzer C, Aberer W, Kranke B. Delayed-type skin reaction to the heparin-alternative danaparoid. J Am Acad Dermatol 2000; 43: 920-2.
    CrossrefPubMedSuche in Google Scholar
  • 30 Trautmann A, Hamm K, Brocker EB. et al. Spattyp-Allergie gegen Heparin. Z Hautkrank 1997; 06: 447-50.
    PubMedSuche in Google Scholar
  • 31 Greinacher A, Warkentin TE. Recognition, treatment, and prevention of heparin-induced thrombocytopenia: Review and update. Thromb Res 2006; 118: 165-76.
    CrossrefPubMedSuche in Google Scholar
  • 32 Warkentin TE. New approaches to the diagnosis of heparin-induced thrombocytopenia. Chest 2005; 127 (Suppl. 02) 35S-45S.
    CrossrefPubMedSuche in Google Scholar
  • 33 Trautmann A, Brocker EB, Klein CE. Intravenous challenge with heparins in patients with delayed-type skin reactions after subcutaneous administration of the drug. Contact Dermatitis 1998; 39: 43-1.
    PubMedSuche in Google Scholar
  • 34 Jappe U, Reinhold D, Bonnekoh B. Arthus reaction to lepirudin, a new recombinant hirudin, and delayed-type hypersensitivity to several heparins and heparinoids, with tolerance to its intravenous administration. Contact Dermatitis 2002; 46: 29-32.
    CrossrefPubMedSuche in Google Scholar
  • 35 Gaigl Z, Pfeuffer P, Raith P. et al. Tolerance to intravenous heparin in patients with delayed-type hypersensitivity to heparins: a prospective study. Br J Haematol 2005; 128: 389-92.
    CrossrefPubMedSuche in Google Scholar
  • 36 Greinacher A, Lubenow N. Recombinant hirudin in clinical practice: Focus on lepirudin. Circulation 2001; 103: 1479-84.
    CrossrefPubMedSuche in Google Scholar
  • 37 Song X, Huhle G, Wang L. et al. Generation of anti-hirudin antibodies in heparin-induced thrombocytopenic patients treated with r-hirudin. Circulation 1999; 100: 1528-32.
    CrossrefPubMedSuche in Google Scholar
  • 38 Huhle G, Hoffmann U, Song X. et al. Immunologic response to recombinant hirudin in HIT type II patients during long-term treatment. Br J Haematol 1999; 106: 195-201.
    CrossrefPubMedSuche in Google Scholar
  • 39 Eichler P, Friesen HJ, Lubenow N. et al. Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood 2000; 96: 2373-8.
    PubMedSuche in Google Scholar
  • 40 Badger NO, Butler K, Hallman LC. Excessive anticoagulation and anaphylactic reaction after rechallenge with lepirudin in a patient with heparin-induced thrombocytopenia. Pharmacotherapy 2004; 24: 1800-3.
    CrossrefPubMedSuche in Google Scholar
  • 41 Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 2003; 108: 2062-5.
    CrossrefPubMedSuche in Google Scholar
  • 42 Bircher AJ, Czendlik CH, Messmer SL. et al. Acute urticaria caused by subcutaneous recombinant hirudin: evidence for an IgG-mediated hypersensitivity reaction. J Allergy Clin Immunol 1996; 98: 994-6.
    CrossrefPubMedSuche in Google Scholar
  • 43 Harenberg J, Huhle G, Wang L. et al. Association of heparin-induced skin lesions, intracutaneous tests, and heparin-induced IgG. Allergy 1999; 54: 473-7.
    CrossrefPubMedSuche in Google Scholar
  • 44 Smith KJ, Rosario-Collazo J, Skelton H. Delayed cutaneous hypersensitivity reactions to hirudin. Arch Pathol Lab Med 2001; 125: 1585-7.
    PubMedSuche in Google Scholar
  • 45 Zollner TM, Gall H, Volpel H. et al. Type IV allergy to natural hirudin confirmed by in vitro stimulation with recombinant hirudin. Contact Dermatitis 1996; 35: 59-60.
    CrossrefPubMedSuche in Google Scholar
  • 46 Bank I, Libourel EJ, Middeldorp S. et al. High rate of skin complications due to low-molecular-weight heparins in pregnant women. J Thromb Haemost 2003; 01: 859-61.
    CrossrefPubMedSuche in Google Scholar
  • 47 Borch JE, Bindslev-Jensen C. Delayed-type hypersensitivity to heparins. Allergy 2004; 59: 118-9.
    PubMedSuche in Google Scholar
  • 48 Bauer KA. Fondaparinux sodium: a selective inhibitor of factor Xa. Am J Health Syst Pharm 2001; 58 (Suppl. 02) S14-S17.
    PubMedSuche in Google Scholar
  • 49 Korstanje MJ, Bessems PJ, Hardy E. et al. Delayed-type hypersensitivity reaction to heparin. Contact Dermatitis 1989; 20: 383-1.
    CrossrefPubMedSuche in Google Scholar
  • 50 Koch P, Schafer H, Bahmer F. lergische Haut-reaktionen gegen Standard- und niedermolekulare He-parine. Z Hautkrank 1991; 66: 435.
    PubMedSuche in Google Scholar
  • 51 Sacher C, Hunzelmann N. Tolerance to the synthetic pentasaccharide fondaparinux in heparin sensitization. Allergy 2003; 58: 1318-9.
    CrossrefPubMedSuche in Google Scholar
  • 52 Maetzke J, Hinrichs R, Staib G. et al. Fondaparinux as anovel therapeutic alternative in a patient with heparin allergy. Allergy 2004; 59: 237-8.
    CrossrefPubMedSuche in Google Scholar
  • 53 Hohenstein E, Tsakiris D, Bircher AJ. Delayed-type hypersensitivity to the ultra-low-molecular-weight heparin fondaparinux. Contact Dermatitis 2004; 51: 149-51.
    CrossrefPubMedSuche in Google Scholar
  • 54 Poza-Guedes P, Gonzalez-Perez R, Canto G. Different patterns of cross-reactivity in non-immediate hypersensitivity to heparins: from localized to systemic reactions. Contact Dermatitis 2002; 47: 244-5.
    CrossrefPubMedSuche in Google Scholar
  • 55 Bauer KA. New anticoagulants: Anti Ha vs anti Xa-Is one better?. J Thromb Thrombolysis 2006; 21: 67-72.
    CrossrefPubMedSuche in Google Scholar
  • 56 Bowler SD, Smith SM, Lavercombe PS. Heparin inhibits the immediate response to antigen in the skin and lungs of allergic subjects. Am Rev Respir Dis 1993; 147: 160-3.
    CrossrefPubMedSuche in Google Scholar
  • 57 Vancheri C, Mastruzzo C, Armato F. et al. Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis. J Allergy Clin Immunol 2001; 108: 703-8.
    CrossrefPubMedSuche in Google Scholar
  • 58 Altinbas M, Coskun HS, Er O. et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2004; 02: 1266-71.
    CrossrefPubMedSuche in Google Scholar
  • 59 Kakkar AK, Levine MN, Kadziola Z. et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS|). J Clin Oncol 4 A.D 10: 1948.
    PubMed
  • 60 Lebeau B, Chastang C, Brechot JM. et al. Subcutaneous heparin treatment increases survival in small cell lung cancer. “Petites Cellules” Group. Cancer 1994; 74: 38-15.
    PubMedSuche in Google Scholar
  • 61 Lemoine NR. Antithrombotic therapy in cancer. J Clin Oncol 2005; 23: 2119-20.
    CrossrefPubMedSuche in Google Scholar
  • 62 Zacharski LR, Ornstein DL. Heparin and cancer. Thromb Haemost 1998; 80: 10-23.
    Thieme ConnectPubMedSuche in Google Scholar
  • 63 Ludwig RJ, Alban S, Bislian R. et al. The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on blood-borne metastasis in vivo . Thromb Haemost 2006; 95: 535-10.
    Thieme ConnectPubMedSuche in Google Scholar
  • 64 Stevenson JL, Choi SHVarkiA. Differential metastasis inhibition by clinically relevant levels of hepa-rins-correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res 2005; 11: 7003-11.
    CrossrefPubMedSuche in Google Scholar