Download PDF
Phlebologie 2010; 39(01): 5-11
DOI: 10.1055/s-0037-1622289
Review
Schattauer GmbH

Heparin-induced skin lesions

More common than suspectedHeparin-induzierte Hautveränderungen sind häufiger als vermutet
M. Schindewolf
1   Department of Internal Medicine, Division of Vascular Medicine and Haemostaseology, Hospital of the Johann Wolfgang Goethe University, Frankfurt am Main, Germany
,
B. Kahle
2   Department of Dermatology, University of Lübeck, Germany
,
E. Lindhoff-Last
1   Department of Internal Medicine, Division of Vascular Medicine and Haemostaseology, Hospital of the Johann Wolfgang Goethe University, Frankfurt am Main, Germany
,
R. J. Ludwig
2   Department of Dermatology, University of Lübeck, Germany
› Author Affiliations
Further Information

Publication History

Received: 18 December 2009

accepted in revised form: 13 January 2010

Publication Date:
05 January 2018 (online)

    Permissions and Reprints

Summary

Cutaneous reactions to subcutaneous heparin injections have been described first in 1952. These reactions may be caused by several mechanisms such as immediate or delayed-type hypersensitivity responses, or by life-threatening immune-mediated heparin-induced thrombocytopenia (HIT). In contrast to bleeding, induction of osteoporosis and hair loss, no data on the incidence and causes of heparin-induced skin lesions had been available until recently. In a large prospective epidemiological study, the incidence of heparin-induced skin lesions was as high as 7.5% in medical patients, far exceeding the expected incidence. As heparin-induced skin lesions may be the sole clinical manifestation of immune HIT, rapid and valid diagnosis of heparin-induced skin lesions is of utmost clinical importance. Therefore, we have reviewed all known causes of heparin-induced skin lesions, and propose diagnostic and therapeutic procedures.

Zusammenfassung

Hautreaktionen auf subkutan appliziertes Heparin wurden erstmals 1952 beschrieben. Hierfür kommt eine Reihe von Ursachen in Frage, am häufigsten sind allergische Reaktionen vom Typ IV und Mikrothromben im Rahmen einer Heparin-indizierten Thrombozytopenie vom Typ II (HIT II) beschrieben worden. Im Gegensatz zu weiteren unerwünschten Arzneimittelwirkungen der Heparine, wie Blutungen, Osteoporose oder Haarausfall, lagen bis vor kurzem keine Daten zur Inzidenz und Ursache Heparin-induzierter Hautveränderungen vor. In einer kürzlich abgeschlossenen prospektiven Untersuchung bei internistischen Patienten betrug die Inzidenz Heparin-induzierter Hautveränderungen 7,5%. Da das initiale klinische Bild Heparin-induzierter Hautveränderungen bei einer lebensbedrohlichen HIT II und einer relativ selbstlimitierenden Typ-IV-allergischen Reaktion ähnlich sind, ist die Differenzierung zwischen beiden Erkrankungen von hoher klinischer Relevanz. Daher stellen wir hier alle bekannten Ursachen Heparin-induzierten Hautveränderungen vor und diagnostische sowie therapeutische Maßnahmen zur Diskussion. Heparin-induzierte Hypersensitivitätsreaktion (HIHS): Dieser Begriff bezeichnet Heparin- induzierte Hautveränderungen im Sinne einer kutanen Typ-IV-Reaktion. Erstes klinisches Zeichen ist Juckreiz im Bereich der Injektionsstellen. Im weiteren Verlauf entwickeln sich dort typische Erytheme und Plaques. In seltenen Fällen kann es zur generalisierten Ausbreitung der Veränderungen kommen. Die Inzidenz der HIHS wird in der Regel unterschätzt. Weibliches Geschlecht und Adipositas gelten als prädisponierende Faktoren. Ebenso bergen langkettige Heparinpräparationen ein höheres Risiko der HIHS. Die Diagnose wird klinisch gestellt – eine ergänzende Histologie ist sinnvoll. Eine allergologische Testung bei HIHS wird nur im Ausnahmefall empfohlen. Immunmediierte Heparin-induzierte Thrombozytopenie (HIT II): Eine schwerwiegende Komplikation der Heparinexposition stellt die immunologische Form der Heparin-induzierten Thrombozytopenie (HIT Typ II oder HIT II) dar, die durch Anti körperbildung hauptsächlich gegen den Komplex aus PF4/Heparin verursacht wird. Die Inzidenz der HIT II wird je nach Patientenkollektiv mit etwa 0,5–5% angegeben, wobei unter niedermolekularen Heparinen wesentlich seltener eine HIT II auftritt als unter unfraktioniertem Heparin. Besonders gefährdet sind Patienten nach kardiochirurgischen Operationen oder größeren orthopädischen Eingriffen. Unter einer HIT II kommt es aufgrund der Thrombozytenaktivierung trotz der sich entwickelnden Thrombozytopenie paradoxerweise zu einer massiven Thromboembolieneigung, so dass die Heparinexposition sofort beendet und auf eine alternative Antikoagulation umgestellt werden muss. Hautveränderungen im Rahmen einer HIT II sind Folge von Verschlüssen der Arteriolen und Venolen. Sie beginnen als blasse Erytheme, die rasch in eine Nekrose übergehen. Heparin-induzierte Soforttypreaktion: Sehr selten treten typische allergische Reaktionen vom Soforttyp im Zusammenhang mit Heparinen auf. Es handelt sich dabei um Urtikaria, Angioödem, Broncho spasmus und schwere Anaphylaxie. Heparin-induzierte bullöse hämorrhagische Dermatose: Bislang wurden 6 Patienten beschrieben, bei welchen es 5–21 Tage nach Einleitung der Heparintherapie zum Auftreten von subcornealen hämorrhagischen Blasen ohne Bezug zum Injektionsort kam. Recall-Urtikaria auf Heparin: In früheren Injektionsstellen kann es unter Heparingabe zu urtikariellen Veränderungen kommen. Für dieses spezifische Gedächtnis spielen Mastzellen eine Rolle. Heparin-induzierte Hautnekrosen unklarer Genese: In einem Fall wurden Heparin-induzierte Haut nekrosen ohne die typischen Zeichen einer HIT II beschrieben. Der Pathomechanismus blieb unklar. Heparin-induzierte Pustulose: Ein Fallbericht liegt vor, der eine heparininduzierte generalisierte Pustulose beschreibt, die sich durch Provokationstestungen reproduzieren ließ. Schlussfolgerung: Heparin-induzierte unerwünschte Nebenwirkungen am Hautorgan sind häufiger als allgemein angenommen. Regelmäßige Untersuchungen der Haut unter Heparintherapie werden daher empfohlen. Alternative Präparate (z. B. Fondaparinux stehen bei Patienten mit dem Risiko eine HIHS oder HIT zu entwickeln zur Verfügung.

Keywords

Heparin - skin - allergy - delayed-type hypersensitivity

Schlüsselwörter

Heparin - Haut - Allergie - allergische Reaktionen Typ IV
 

  • References

  • 1 Agnelli G, Bergqvist D, Cohen AT, Gallus AS, Gent M. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg 2005; 92: 1212-1220.
    CrossrefPubMedGoogle Scholar
  • 2 Ahmed T, Garrigo J, Danta I. Preventing bronchoconstriction in exercise-induced asthma with inhaled heparin. N Engl J Med 1993; 329: 90-95.
    CrossrefPubMedGoogle Scholar
  • 3 Alban S. Carbohydrates with anticoagulant and antithrombotic properties. In: Witczak ZJ, Nieforth KA. (eds) Carbohydrates in drug design. New York: Marcel Dekker; 1997: 209-276.
    Google Scholar
  • 4 Alban S. From heparins to factor Xa inhibitors and beyond. Eur J Clin Invest 2005; 35: 12-20.
    CrossrefPubMedGoogle Scholar
  • 5 Alban S, Ludwig RJ, Bendas G, Schön MP, Oostingh GJ, Radeke HH, Fritzsche J, Pfeilschifter J, Kaufmann R, Boehncke WH. PS3, A semisynthetic beta-1,3-glucan sulfate, diminishes contact hypersensitivity responses through inhibition of L- and P-selectin functions. J Invest Dermatol 2009; 129: 1192-1202.
    CrossrefPubMedGoogle Scholar
  • 6 Anderson CL, Chacko GW, Osborne JM, Brandt JT. The Fc receptor for immunoglobulin G (Fc gamma RII) on human platelets. Semin Thromb Hemost 1995; 21: 1-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Andersson LO, Barrowcliffe TW, Holmer E, Johnson EA, Sims GE. Anticoagulant properties of heparin fractionated by affinity chromatography on matrix-bound antithrombin 3 and by gel filtration. Thromb Res 1976; 9: 575-583.
    CrossrefPubMedGoogle Scholar
  • 8 Bank I, Libourel EJ, Middeldorp S, Van Der MJ, Buller HR. High rate of skin complications due to low-molecular-weight heparins in pregnant women. J Thromb Haemost 2003; 1: 859-861.
    CrossrefPubMedGoogle Scholar
  • 9 Bauer KA, Eriksson BI, Lassen MR, Turpie AG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305-1310.
    CrossrefPubMedGoogle Scholar
  • 10 Bauer KA, Hawkins DW, Peters PC, Petitou M, Herbert JM, van Boeckel CA, Meuleman DG. Fondaparinux, a synthetic pentasaccharide: the first in a new class of antithrombotic agents – the selective factor Xa inhibitors. Cardiovasc Drug Rev 2002; 20: 37-52.
    CrossrefPubMedGoogle Scholar
  • 11 Beltraminelli H, Itin P, Cerroni L. Intraepidermal bullous haemorrhage during anticoagulation with low-molecular-weight heparin: two cases. Br J Dermatol 2009; 161: 191-193.
    PubMedGoogle Scholar
  • 12 Bircher AJ, Harr T, Hohenstein L, Tsakiris DA. Hypersensitivity reactions to anticoagulant drugs: diagnosis and management options. Allergy 2006; 61: 1432-1440.
    CrossrefPubMedGoogle Scholar
  • 13 Björg I, Olson ST, Shore JD. Molecular mechanisms of the accelerating effect on the reactions between antithrombin and clotting proteases. In: Lane DA, Lindahl U. (eds) Heparin, chemical and biological properties, clinical applications. Boca Raton, Fl: CRC Press; 1989: 229-256.
    Google Scholar
  • 14 Bloom B, Chalmers PC, Danker PR, Kumar S, Sheikh F. Cardiovascular collapse and refractory bronchospasm following administration of vancomycin, esmolol, and heparin. J Cardiothorac Anesth 1989; 3: 748-751.
    CrossrefPubMedGoogle Scholar
  • 15 Borsig L, Wong R, Feramisco J, Nadeau DR, Varki NM, Varki A. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc Natl Acad Sci USA 2001; 98: 3352-3357.
    CrossrefPubMedGoogle Scholar
  • 16 Caliskaner Z, Karaayvaz M, Ozturk S. Recurrent urticaria lesions in a heparin-allergic patient: most likely another form of „recall urticaria“. J Investig Allergol Clin Immunol 2005; 15: 78-80.
    PubMedGoogle Scholar
  • 17 Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W, Turpie AG, Egberts JF, Lensing AW. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. Br Med J 2006; 332: 325-329.
    CrossrefPubMedGoogle Scholar
  • 18 Cosgrove RH, Zacharski LR, Racine E, Andersen JC. Improved cancer mortality with low-molecular-weight heparin treatment: a review of the evidence. Semin Thromb Hemost 2002; 28: 79-87.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Crafoord C. Preliminary report on postoperative treatment with heparin as a preventive of thrombosis. Acta Chir Scand 1937; 79: 407-426.
    Google Scholar
  • 20 Demir M, Iqbal O, Dietrich CP, Hoppensteadt DA, Ahmad S, Daud AN, Fareed J. Anticoagulant and antiprotease effects of a novel heparinlike compound from shrimp (Penaeus brasiliensis) and its neutralization by heparinase I. Clin Appl Thromb Hemost 2001; 7: 44-52.
    CrossrefPubMedGoogle Scholar
  • 21 Eriksson BI, Bauer KA, Lassen MR, Turpie AG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345: 1298-1304.
    CrossrefPubMedGoogle Scholar
  • 22 Francis CW. Clinical practice. Prophylaxis for thromboembolism in hospitalized medical patients. N Engl J Med 2007; 356: 1438-1444.
    CrossrefPubMedGoogle Scholar
  • 23 Greinacher A. Antigen generation in heparin-associated thrombocytopenia: the non-immunologic type and the immunologic type are closely linked in their pathogenesis. Semin Thromb Hemost 1995; 21: 106-116.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Greinacher A, Alban S, Dummel V, Franz G, Mueller-Eckhardt C. Characterization of the structural requirements for a carbohydrate based anticoagulant with a reduced risk of inducing the immunological type of heparin-associated thrombocytopenia. Thromb Haemost 1995; 74: 886-892.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Grims RH, Weger W, Reiter H, Arbab E, Kranke B, Aberer W. Delayed-type hypersensitivity to low molecular weight heparins and heparinoids: cross-reactivity does not depend on molecular weight. Br J Dermatol 2007; 157: 514-517.
    CrossrefPubMedGoogle Scholar
  • 26 Hach-Wunderle V, Kainer K, Krug B, Müller-Berghaus G, Pötzsch B. Heparin-associated thrombosis despite normal platelet counts. Lancet 1994; 344: 469-470.
    PubMedGoogle Scholar
  • 27 Harenberg J, Huhle G, Wang L, Hoffmann U, Bayerl C, Kerowgan M. Association of heparin-induced skin lesions, intracutaneous tests, and heparin-induced IgG. Allergy 1999; 54: 473-477.
    CrossrefPubMedGoogle Scholar
  • 28 Harr T, Scherer K, Tsakiris DA, Bircher AJ. Immediate type hypersensitivity to low molecular weight heparins and tolerance of unfractioned heparin and fondaparinux. Allergy 2006; 61: 787-788.
    CrossrefPubMedGoogle Scholar
  • 29 Hill J, Treasure T. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients having surgery: summary of NICE guidance. Br Med J 2007; 334: 1053-1054.
    CrossrefPubMedGoogle Scholar
  • 30 Hirsh J, Guyatt G, Albers GW, Harrington R, Schunemann HJ. Executive summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133: 71S-109S.
    CrossrefPubMedGoogle Scholar
  • 31 Jappe U. Allergy to heparins and anticoagulants with a similar pharmacological profile: an update. Blood Coagul Fibrinolysis 2006; 17: 605-613.
    CrossrefPubMedGoogle Scholar
  • 32 Jorpes E. The chemistry of heparin. Biochem J 1935; 29: 1817-1830.
    CrossrefPubMedGoogle Scholar
  • 33 Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, Rustin G, Thomas M, Quigley M, Williamson RC. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol 2004; 10: 1948.
    Google Scholar
  • 34 Kingery FA. Osteoporosis, fractures, and heparin therapy. JAMA 1965; 193: 152.
    PubMedGoogle Scholar
  • 35 Kishimoto TK, Viswanathan K, Ganguly T, Elankumaran S, Smith S, Pelzer K, Lansing JC, Sriranganathan N, Zhao G, Galcheva-Gargova Z, Al-Hakim A, Bailey GS, Fraser B, Roy S, Rogers-Cotrone T, Buhse L, Whary M, Fox J, Nasr M, Dal Pan GJ, Shriver Z, Langer RS, Venkataraman G, Austen KF, Woodcock J, Sasisekharan R. Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med 2008; 358: 2457-67.
    CrossrefPubMedGoogle Scholar
  • 36 Kneilling M, Rocken M. Mast cells: novel clinical perspectives from recent insights. Exp Dermatol 2009; 18: 488-496.
    CrossrefPubMedGoogle Scholar
  • 37 Komericki P, Grims RH, Kränke B, Aberer W. Acute generalized exanthematous pustolosis from dalteparin. J Am Acad Dermatol 2007; 57: 718-721.
    CrossrefPubMedGoogle Scholar
  • 38 Lassen MR, Bauer KA, Eriksson BI, Turpie AG. Post-operative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002; 359: 1715-1720.
    CrossrefPubMedGoogle Scholar
  • 39 Lebeau B, Chastang C, Brechot JM, Capron F, Dautzenberg B, Delaisements C, Mornet M, Brun J, Hurdebourcq JP, Lemarie E. Subcutaneous heparin treatment increases survival in small cell lung cancer. „Petites Cellules“ Group. Cancer 1994; 74: 38-45.
    CrossrefPubMedGoogle Scholar
  • 40 Li ZQ, Liu W, Park KS, Sachains BS, Arepally GM, Cines DB, Poncz M. Defining a second epitope for heparin-induced thrombocytopenia/thrombosis antibodies using KKO, a murine HIT-like monoclonal antibody. Blood 2002; 99: 1230-1236.
    CrossrefPubMedGoogle Scholar
  • 41 Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006; 4: 759-765.
    CrossrefPubMedGoogle Scholar
  • 42 Lopez S, Torres MJ, Rodriguez-Pena R, Blanca-Lopez N, Fernandez TD, Antunez C, Canto G, de L V, Mayorga C. Lymphocyte proliferation response in patients with delayed hypersensitivity reactions to heparins. Br J Dermatol 2009; 160: 259-265.
    CrossrefPubMedGoogle Scholar
  • 43 Ludwig RJ, Alban S, Bislian R, Kaufmann R, Diehl S, Henschler R, Boehncke WH, Gille J. 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: 535-540.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Ludwig RJ, Alban S, Boehncke WH. Structural requirements of heparin and related molecules to exert a multitude of anti-inflammatory activities. Mini Rev Med Chem 2006; 6: 1009-1023.
    CrossrefPubMedGoogle Scholar
  • 45 Ludwig RJ, Boehme B, Podda M, Tandi C, Jager E, Henschler R, Boehncke WH, Zollner TM, Kaufmann R, Gille J. Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis. Cancer Res 2004; 64: 2743-2750.
    CrossrefPubMedGoogle Scholar
  • 46 Ludwig RJ, Schindewolf M, Alban S, Kaufmann R, Lindhoff-Last E, Boehncke WH. Molecular weight determines the frequency of delayed type hypersensitivity reactions to heparin and synthetic oligosaccharides. Thromb Haemost 2005; 94: 1265-1269.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Ludwig RJ, Schindewolf M, Lindhoff-Last E, Boehncke WH. The influence of heparin's molecular weight and the incidence of delayed type hypersensitivity reactions revisited; in response to Grims et al. Br J Dermatol 2007; 157:514–17 Br J Dermatol 2008; 158: 849-851.
    CrossrefPubMedGoogle Scholar
  • 48 Ludwig RJ, Schindewolf M, Utikal J, Lindhoff-Last E, Boehncke WH. Management of cutaneous type IV hypersensitivity reactions induced by heparin. Thromb Haemost 2006; 96: 611-617.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Ludwig RJ, Schön MP, Boehncke WH. P-selectin: a common therapeutic target for cardiovascular disorders, inflammation and tumour metastasis. Expert Opin Ther Targets 2007; 11: 1103-1117.
    CrossrefPubMedGoogle Scholar
  • 50 Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106: 2710-2715.
    CrossrefPubMedGoogle Scholar
  • 51 Mehran R, Lansky AJ, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Wong SC, Nikolsky E, Gambone L, Vandertie L, Parise H, Dangas GD, Stone GW. Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. Lancet 2009; 374: 1149-1159.
    CrossrefPubMedGoogle Scholar
  • 52 Perrinaud A, Jacobi D, Machet MC, Grodet C, Gruel Y, Machet L. Bullous hemorrhagic dermatosis occurring at sites distant from subcutaneous injections of heparin: three cases. J Am Acad Dermatol 2006; 54: S5-S7.
    CrossrefPubMedGoogle Scholar
  • 53 Plancherel P. Klinische und gerinnungsphysiologische Untersuchungen mit einem neuem Heparin depotpräparat. Z Klin Med 1952; 150: 213-259.
    Google Scholar
  • 54 Schindewolf M, Lindhoff-Last E. Fondaparinux-related thrombocytopenia in a patient with former HIT. Thromb Haemost 2008; 100: 168-169.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 55 Schindewolf M, Ludwig RJ, Wolter M, Himsel A, Zgouras D, Kaufmann R, Boehncke WH, Lindhoff-Last E. Tolerance of fondaparinux in patients with generalized contact dermatitis to heparin. J Eur Acad Dermatol Venereol 2008; 22: 378-380.
    CrossrefPubMedGoogle Scholar
  • 56 Schindewolf M, Schwaner S, Wolter M, Kroll H, Kaufmann R, Boehncke WH, Lindhoff-Last E, Ludwig RJ. Incidence and causes of heparin-induced skin lesions. CMAJ 2009; 181: 477-481.
    CrossrefPubMedGoogle Scholar
  • 57 Sculpher MJ, Lozano-Ortega G, Sambrook J, Palmer S, Ormanidhi O, Bakhai A, Flather M, Steg PG, Mehta SR, Weintraub W. Fondaparinux versus Enoxaparin in non-ST-elevation acute coronary syndromes: short-term cost and long-term cost-effectiveness using data from the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators (OASIS-5) trial. Am Heart J 2009; 157: 845-852.
    CrossrefPubMedGoogle Scholar
  • 58 Singh S, Verma M, Bahekar A, Agrawal P, Duggal J, Ilescu M, Khosla P, Muzaffar S. Enoxaparin-induced skin necrosis: a fatal outcome. Am J Ther 2007; 14: 408-410.
    CrossrefPubMedGoogle Scholar
  • 59 Stevenson JL, Choi SH, Varki A. Differential metastasis inhibition by clinically relevant levels of heparins--correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res 2005; 11: 7003-7011.
    CrossrefPubMedGoogle Scholar
  • 60 Suh JS, Aster RH, Visentin GP. Antibodies from patients with heparin-induced thrombocytopenia/ thrombosis recognize different epitopes on heparin: platelet factor 4. Blood 1998; 91: 916-922.
    PubMedGoogle Scholar
  • 61 Thuillier D, Chaby G, Dadban A, Dascotte E, Miquel-Christophe O, Andrejak M, Chatelain D, Lok C. Low-molecular-weight heparin-induced bullous haemorrhagic dermatosis associated with cell-mediated hypersensitivity. Ann Dermatol Venereol 2009; 136: 705-708.
    CrossrefPubMedGoogle Scholar
  • 62 Tiu A, Pang JM, Martin R, Officer N. Allergic reactions to enoxaparin and heparin: a case report and review of the literature. N Z Med J 2004; 117: U1126.
    PubMedGoogle Scholar
  • 63 Uncu H. A comparison of low-molecular-weight heparin and combined therapy of low-molecular-weight heparin with an anti-inflammatory agent in the treatment of superficial vein thrombosis. Phlebology 2009; 24: 56-60.
    CrossrefPubMedGoogle Scholar
  • 64 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.
    CrossrefPubMedGoogle Scholar
  • 65 Warkentin TE. Heparin-induced skin lesions. Br J Haematol 1996; 92: 494-497.
    CrossrefPubMedGoogle Scholar
  • 66 Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A. (eds). Heparin-induced thrombocytopenia. New York: Marcel Dekker; 2004: 53-106.
    Google Scholar
  • 67 Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 311S-337S.
    CrossrefPubMedGoogle Scholar
  • 68 Warkentin TE, Greinacher A. Heparin-induced anaphylactic and anaphylactoid reactions: two distinct but overlapping syndromes. Expert Opin Drug Saf 2009; 8: 129-144.
    CrossrefPubMedGoogle Scholar
  • 69 Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133: 340S-380S.
    CrossrefPubMedGoogle Scholar
  • 70 Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med 2007; 356: 2653-2655.
    CrossrefPubMedGoogle Scholar
  • 71 Warkentin TE, Roberts RS, Hirsh J, Kelton JG. Heparin-induced skin lesions and other unusual sequelae of the heparin-induced thrombocytopenia syndrome: a nested cohort study. Chest 2005; 127: 1857-1861.
    CrossrefPubMedGoogle Scholar
  • 72 Weber HO, Fischer J, Kneilling M, Caroli U, Rocken M, Biedermann T. Recall urticaria induced by skin tests with heparin. Br J Dermatol 2009; 161: 187-189.
    PubMedGoogle Scholar