Hypersensitivity reactions to LMWHs: different patterns of cross-reactivity in three patients. Case series and a literature review.

Transcription

1 Hypersensitivity reactions to LMWHs: different patterns of cross-reactivity in three patients. Case series and a literature review. Journal: Canadian Journal of Physiology and Pharmacology Manuscript ID cjpp r1 Manuscript Type: Brief Report Date Submitted by the Author: 17-Jul-2017 Complete List of Authors: Juricic Nahal, Danica; University Hospital Centre Zagreb, Division of Clinical Pharmacology; Agency for Medicinal Products and Medical Devices of Croatia Cegec, Ivana; University Hospital Centre Zagreb, Division of Clinical Pharmacology Erdeljic Turk, Viktorija; University Hospital Centre Zagreb, Division of Clinical Pharmacology Makar Ausperger, Ksenija; University Hospital Centre Zagreb, Division of Clinical Pharmacology Kraljickovic, Iva; University Hospital Centre Zagreb, Division of Clinical Pharmacology Simic, Iveta; University Hospital Centre Zagreb, Division of Clinical Pharmacology; University of Zagreb School of Medicine Is the invited manuscript for consideration in a Special Issue?: Keyword: N/A cross-reactivity, delayed-type hypersensitivity reactions (DHR), immediatetype hypersensitivity reactions (IHR), low molecular weight heparins (LMWH), skin tests

2 Page 1 of 12 Canadian Journal of Physiology and Pharmacology Hypersensitivity reactions to LMWHs: different patterns of cross-reactivity in three patients. Case series and a literature review. Short title: Hypersensitivity reactions to LMWHs Danica Juricic Nahal MD 1,3 *, Ivana Cegec MD 1, Viktorija Erdeljic Turk MD, PhD 1, Ksenija Makar Ausperger MD, PhD 1, Iva Kraljickovic MD, Iveta Simic MD, PhD 1,2 1 Zagreb, Zagreb, Croatia 2 University of Zagreb School of Medicine, Zagreb, Croatia 3 Agency for Medicinal Products and Medical Devices of Croatia * Corresponding author: Danica Juricic Nahal MD Zagreb, Kispaticeva 12, Zagreb, Croatia and Agency for Medicinal Products and Medical Devices of Croatia, Ksaverska cesta 4, Zagreb, Croatia danica.juricic@gmail.com Ivana Cegec MD Zagreb, Kispaticeva 12, Zagreb, Croatia ivanacegec@gmail.com Viktorija Erdeljic Turk MD, PhD Zagreb, Kispaticeva 12, Zagreb, Croatia verdeljic@gmail.com Ksenija Makar Ausperger MD, PhD Zagreb, Kispaticeva 12, Zagreb, Croatia ksenijamakar@gmail.com Iva Kraljickovic MD Zagreb, Kispaticeva 12, Zagreb, Croatia ivakraljickovic@gmail.com Iveta Simic MD, PhD Zagreb, Kispaticeva 12, Zagreb, Croatia and University of Zagreb School of Medicine, Salata 3, Zagreb, Croatia imercep@gmail.com

3 Page 2 of 12 Abstract Low molecular weight heparins (LMWH) are used for a variety of indications. The most common type of hypersensitivity reactions to LMWHs are delayed-type hypersensitivity reactions (DHR). Immediate-type hypersensitivity reactions (IHR) occur only sporadically. Cross-reactivity of different LMWHs is a common and unpredictable problem. We present two cases of patients who developed DHR to nadroparin and enoxaparin, respectively. The third case presents a patient who developed IHR to nadroparin. Skin tests confirmed the hypersensitivity in all cases. In the cases of DHR, a skin test negative LMWH was identified and was tolerated in a challenge test. In the IHR case, crossreactivity to all tested LMWHs was established. We hypothesize that the degree of cross-reactivity might depend on the type of hypersensitivity reaction with immediate reactions linked to more extensive cross-reactivity than delayed reactions. This is important to consider since, at least in some cases, a safe alternative LMWH can be identified. KEYWORDS: Cross-reactivity, Delayed-type hypersensitivity reactions (DHR), Immediate-type hypersensitivity reactions (IHR), Low molecular weight heparins (LMWH), Skin tests

4 Page 3 of 12 Canadian Journal of Physiology and Pharmacology Manuscript text Introduction Low molecular weight heparins (LMWH) are used daily for a variety of indications. Although considered safe medications, hypersensitivity reaction can occur. The most common type of hypersensitivity reactions to LMWHs are delayed-type hypersensitivity reactions (DHR) which are reported in up to 10% of patients (Schindewolf et al. 2009; Schindewolf et al. 2013). Clinical manifestations of DHR include erythematous plaques and maculopapular exanthemas at the injection site. Immediate-type hypersensitivity reactions (IHR) to LMWHs are extremely rare and are limited to case reports (Gonzalez-Delgado and Fernandez 2016; MacLaughlin et al. 2002; Anders and Trautmann 2013; Leguísamo et al. 2015). Clinical manifestations of IHR include urticaria, hypotension, angioedema, pruritus and anaphylaxis. Skin tests including prick and intradermal test followed by a subcutaneous challenge test have been performed to establish the diagnosis of hypersensitivity to LMWHs and are generally recommended (Bircher et al. 2006; Brockow et al. 2013). Testing is contraindicated in cases of heparin induced thrombocytopenia (HIT). The problem of cross-reactivity among different LMWHs has been widely recognised and is reported in the literature in up to 89.7% of patients (Weberschock et al. 2011; Grassegger et al. 2001). Identification of a subset of patients who can tolerate an alternative LMWH after a hypersensitivity reaction to a single LMWH would be of great clinical value. However, literature on such successful identifications is limited. Methods Skin test procedures at our Department are based on European Network for Drug Allergy (ENDA) publications (Brockow et al. 2002; Brockow et al. 2013). Prick tests are performed using undiluted commercially available LMWH preparations. Histamine is used as a positive, and 0.9% saline as a negative control. Readings are done after 10 minutes for histamine and after 20 minutes for tested LMWHs. Following negative results, intradermal tests are performed with LMWHs diluted to 1:10. Readings are done after 20 minutes (immediate reading) and on days 2, 3 and 7 (delayed readings). Immediate readings are considered positive if the size of the initial wheal increases by at least 3 mm in diameter after 20 minutes. Delayed readings are considered positive if the presence of infiltrated erythema is observed. After the completion of skin tests, a skin-test negative preparation is chosen for the subcutaneous challenge test. Undiluted LMWH is injected subcutaneously in the lower abdominal area with readings after 20 minute (immediate) and on days 2, 3 and 7 (delayed readings). Results (Case reports) Case No 1 presents a 40-year old female patient with a history of previous exposure to LMWH who developed generalised erythematous itchy plaques in 2015 after the administration of nadroparin prophylactically following knee surgery. The reaction developed after 2 days of nadroparin administration, but the exact time elapsed from the last nadroparin injection to the development of the cutaneous reaction could not be established. She was evaluated at our Department in June After obtaining a written consent, skin tests to dalteparin, nadroparin and enoxaparin were performed. Following negative prick tests to all tested heparins, intradermal tests (ID) were

5 Page 4 of 12 performed and immediate readings were positive to nadroparin and dalteparin. Since ID tests to enoxaparin were negative, a subcutaneous challenge test with enoxaparin (1000 IU, 0.1ml) with immediate and delayed readings on days 0, 2, 3 and 7 was performed. All delayed readings were negative. Enoxaparin was well tolerated and provoked neither an immediate nor a delayed skin reaction. The patient was provided with written advice to avoid nadroparin and dalteparin while enoxaparin can be used as indicated. Case No 2 presents a 43-year old female patient who developed a skin reaction (without additional details provided) after 7 days of prophylactic treatment with enoxaparin due to a history of several miscarriages in June The exact time elapsed from the seventh injection of enoxaparin to the onset of the skin reaction could not be established. After the onset of the reaction the patient was switched to nadroparin. Nadroparin was administered for 2 days but was discontinued due to the persistence of the skin reaction. Further use of LMWHs was not deemed necessary since the patient experienced another miscarriage while on LMWH therapy. She was evaluated at our Department in September After obtaining a written consent, skin tests to dalteparin, nadroparin and enoxaparin were performed. Following negative prick test, ID test were performed. Immediate readings were negative to enoxaparin and dalteparin and positive to nadroparin. In the delayed readings on days 2, 3 and 7, the sites of ID test to enoxaparin showed redness and itching and a delayed-type of hypersensitivity to enoxaparin was established. Delayed readings of ID test to nadroparin and dalteparin were negative. A subcutaneous challenge test with dalteparin (1250 IU, 0.1ml) was then performed with immediate and delayed readings. Dalteparin was well tolerated and provoked neither an immediate nor a delayed skin reaction. The patient was provided with written advice to avoid nadroparin and enoxaparin while dalteparin can be used as indicated. Case No 3 presents a 35-year old female patient who developed a severe skin reaction (documented as such in the discharge letter from the local hospital) after the administration of nadroparin prophylactically for a breast fibroadenoma removal in September The patient recalls the development of generalised skin redness. The reaction occurred several minutes after the administration of the first dose of nadroparin, and her surgery was cancelled. Her past medical history was remarkable for chronic urticaria that was inactive at the time of the reaction. She was evaluated at our Department in October After obtaining a written consent, skin tests to dalteparin, nadroparin and enoxaparin were performed. Twenty minutes after prick tests were performed; the development of a few erythematous plaques was noted. Since the skin area around the prick tests was unaffected, it was decided to proceed with intradermal tests. The immediate reading was positive for nadroparin and negative for other tested heparins. However, in the following 2 hours the patient developed generalised urticaria that required treatment with oral antihistamines and corticosteroids. Urticaria subsided in the course of the following few days. The patient was re-evaluated at our Department 7 months after the initial testing. The same procedure for skin test was followed except that each heparin was tested on a separate day. Skin tests to both dalteparin and enoxaparin were positive in the immediate readings and produced generalised urticaria. A diagnosis of immediate- type hypersensitivity LMWHs was made and cross-reactivity to all tested LMWHs was confirmed. The patient was provided with written advice to avoid all LMWHs. A summary of results is available in Table 1. Discussion

6 Page 5 of 12 Canadian Journal of Physiology and Pharmacology The exact mechanism of hypersensitivity reactions to LMWHs is unknown. It has been proposed that each heparin carries an individual, drug-specific risk for inducing hypersensitivity reactions. Evidence in support of this proposal is limited (Brockow et al. 2002). Cross-reactivity of different LMWHs is a well-known problem. However, it is impossible to predict the pattern of cross-reactivity among different LMWHs since the it does not seem to depend on the molecular weight of heparins (Weberschock et al. 2011). Due to a limited number of published reports with negative challenge tests (for DHR) and a very low prevalence of IHR, cross-reactivity to other LMWHs has not yet been explained (Canti et al. 2015; Bircher et al. 1995). We present two cases of DHR in which cross-reactivity studies have been performed, and tolerance of a skin test negative LMWH has been proven. In Case 1, cross-reactivity was established between nadroparin and dalteparin while enoxaparin was tolerated in a subcutaneous challenge test. In Case 2, cross-reactivity was established between enoxaparin and nadroparin while dalteparin was tolerated in a subcutaneous challenge test. Our two cases are consistent with other published cases of DHR. Canti describes a case of crossreactivity between enoxaparin and nadroparin while dalteparin was tolerated in a subcutaneous challenge test which is identical to our Case 2 (Canti et al. 2015). Colom describes 3 cases of DHR to LMWHs (Palacios Colom et al. 2008). The first case describes complete cross-reactivity among the tested LMWHs (nadroparin, dalteparin, enoxaparin and bemiparin). The second case describes crossreactivity between nadroparin and dalteparin, while skin tests remained negative to bemiparin and enoxaparin. However, tolerance to bemiparin and enoxaparin cannot be established since challenge tests have not been performed. The third case describes cross-reactivity between enoxaparin and dalteparin. Skin tests remained negative to nadroparin and bemiparin. However, challenge test was positive for bemiparin, while tolerance to nadroparin cannot be established since challenge test was not done. Grassegger describes 13 cases of DHR to different LMWHs (Grassegger et al. 2001). Patients were tested subcutaneously to several LMWHs. Although details are not provided, the results of the study indicate that complete cross-reactivity to all tested heparins was established in 4 cases while no cross-reactivity among LMWHs was found in 7 cases. In the remaining 2 cases, crossreactivity was found between 2 LMWHs but at least one other test-negative LMWH could be identified. An important advantage of our DHR cases is the performance of challenge tests. This has important clinical value, since a safe LMWH has been identified for future use. We could argue that the challenge dose should have been higher or that the true tolerance could only be established after a course of LMWH and a follow-up. Although that would certainly add strength to our cases, our report is done in a retrospective way and as such carries imperfections that do not underrate its overall scientific contribution. In cases 2 and 3, we were able to adhere to the optimal time period for performance of skin tests (between 3 weeks and 3 months after the reaction) (Brockow et al. 2002). An inadvertent variation occurred in the testing protocol for Case 1 compared to Cases 3 and 4. In Case 1, challenge test was done on the same day as the intradermal tests, and the delayed readings were performed parallel to ID and challenge tests. Since all ID and challenge test were negative, this protocol variation did not influence the validity of the final results. The third case presents a very rare case of IHR to one LMWH with cross-reactivity to other two tested LMWHs. Literature search revealed only seven cases of proven immediate-type

7 Page 6 of 12 hypersensitivity to the culprit LMWH where skin cross-reactivity studies were done and information on the results has been provided (Anders and Trautmann 2013; Caballero and Fernandez-Benitez 2003; González et al. 2014; Harr et al. 2006; Bekkenk and van Zuuren 2005; Cesana et al. 2016; Kavut and Koca 2012). The cases are summarised in Table 2. Anders describes a case of IHR to enoxaparin with cross-reactivity to nadroparin but negative skin tests to dalteparin (Anders and Trautmann 2013). However, since only prick tests have been performed, a conclusion on tolerance of dalteparin cannot be made. Moreover, the authors do not state the time elapsed from the anaphylactic reaction to testing. This is an important missing information since the testing should be postponed until the resolution of clinical symptoms and clearance of the incriminated drug and of the antiallergic medications from the circulation (Brockow et al. 2002). Caballero describes two cases of IHR to enoxaparin (Caballero and Fernandez-Benitez 2003). However, for the purpose of this review only one case (with positive skin tests to culprit drug) is considered relevant. Although prick tests to enoxaparin and nadroparin were negative, immediate and delayed readings of intradermal tests to both LMWHs were positive. The authors found positive ID tests to calcium heparin and presented a novel in vitro diagnostic technique, the basophil activation test (BAT). Since only 2 LMWHs were tested in this case, a more detailed insight into the patterns of cross-reactivity could not be made. Gonzalez describes a case of IHR to bemiparin and enoxaparin (González et al. 2014). Skin tests were done for several LMWHs (enoxaparin, bemiparin, dalteparin, nadroparin, tinzaparin) UFH, fondaparinux and lepirudin. Intradermal tests were positive for all LMWHs and negative for all other tested drugs. Challenge tests confirmed tolerance of UFH, fondaparinux and lepirudin. Harr describes a case of IHR to dalteparin (Harr et al. 2006). Skin tests were positive for all tested LMWHs (dalteparin, nadroparin, enoxaparin) but were negative to UFH, danaparoid, lepirudin and fondaparinux. Challenge tests confirmed tolerance of UFH and fondaparinux. Time elapsed from the anaphylactic reaction to testing is not stated. Bekkenk describes a case of IHR to nadroparin that showed cross-reactivity to dalteparin but skin tests were negative to enoxaparin and tinzaparin. However, challenge with enoxaparin resulted in generalised urticaria, so the skin test was presumably falsely negative and the tolerance of tinzaparin could not be established since challenge test was not performed (Bekkenk and van Zuuren 2005). Cesana describes two cases of IHR to dalteparin (Cesana et al. 2016). For the purpose of this review only one case (with positive skin tests to culprit drug) is considered relevant. Skin tests were positive to dalteparin, nadroparin and enoxaparin and negative for UFH and fondaparinux. The tolerance of the latter two drugs was confirmed with a challenge test. Kavut describes a case of IHR to enoxaparin (Kavut and Koca 2012). Skin tests were positive to enoxaparin but negative to other tested LMWHs (nadroparin, dalteparin, tinzaparin). However, challenge tests were positive for the 3 skin test negative LMWHs. The reason for the unexpected results of challenge tests might be in the fact that testing was done shortly after the reaction. If skin tests are performed within the next few days of the reaction, testing is considered unreliable and might be falsely negative due to histamin depletion (Brockow et al. 2002). Our Case 3 is consistent with other published cases of IHR to a LMWH. An advantage of our case is adherence to the recommendation about timing of skin tests. Moreover, our patient underwent the testing procedure twice with the same end result, which adds to the credibility of the results. Not including UFH and fondaparinux might be perceived as a shortcoming of our case. Although this would be of benefit, our patient subsequently underwent the fibroadenoma removal without anticoagulation and was unwilling to proceed with further testing.

8 Page 7 of 12 Canadian Journal of Physiology and Pharmacology Weberschock proposes that a differential degree of cross-reactivity might depend on the anticoagulant inducing the DHR (Weberschock et al. 2011). We additionally propose that the degree of cross-reactivity might depend on the type of hypersensitivity reaction elicited. Although based on only eight cases altogether, we hypothesize that in the case of immediate hypersensitivity reactions to a LMWH, cross-reactivity to all available LMWHs should be assumed. On the other hand, in the case of delayed-type hypersensitivity reactions to a LMWH, a safe alternative LMWH can sometimes be identified and complete cross-reactivity seems less likely. In the case of cross-reactivity to all LMWHs, several options exist. The patient could be switched to oral anticoagulants, fondaparinux or other anticoagulants might be used, and even intravenous administration of UFH might be tolerated. However, the administration of other parenteral anticoagulants should be discouraged without prior testing since broader cross-reactivity is possible. Desensitization might be considered for patients with IHR to a LMWH and a complete crossreactivity to the drug class. Our literature search revealed three cases of successful desensitization with un-fractionated heparin in patients who experienced IHR to heparins (LMWHs in two cases and UFH in one case) (Kavut and Koca 2012; Altintaş et al. 2009; Parekh et al. 2005). However, to the best of our knowledge there are no published cases of desensitization with LMWHs. The decision to proceed with desensitization is made if alternative medications are not available or are of inferior therapeutic efficacy. In our Case 3, additional testing to fondaparinux and UFH should be performed prior to possible desensitization. Further studies are necessary in the field of cross-reactivity to LMWHs. The studies should optimally include patients with IHR in whom different available parenteral heparins are tested following the principles set out in the relevant literature. More published cases of IHR to a LMWH would allow us to identify a possible pattern of cross-reactivity and would enable us to test the hypothesis of different degree of cross-reactivity based on the type of reaction elicited. Conclusion In conclusion, a definite diagnosis of hypersensitivity to LMWHs should be established in order to guide further anticoagulant treatment. The diagnosis is based on history and skin tests, and tolerance is proven with a challenge test. We suggest that patients with DHRs to LMWHs be evaluated by means of skin tests to all available LMWHs and that the challenge tests are performed with a skin test negative LMWH. Different LMWHs show broad, but not complete cross-reactivity. The cross-reactivity is unpredictable, linked to the culprit LMWH and possibly to the type of initial reaction. At least in some cases, a safe alternative LMWH can be identified in patients who have experienced a DHR to a LMWH. Our observation of different cross-reactivity patterns based on the type of hypersensitivity reaction (immediate vs. delayed) should be further investigated.

9 Page 8 of 12 References Altintaş N.D., Aybar Türkoğlu M., Bozkurt B. et al Successful heparin desensitization after anaphylactic shock due to heparin. Tuberk Toraks. 57(1): Anders D., Trautmann A Allergic anaphylaxis due to subcutaneously injected heparin. Allergy Asthma Clin Immunol. 10;9(1):1. doi: / Bekkenk M.W., van Zuuren E.J Immediate type hypersensitivity after injection of nadroparine (Fraxiparin). Thromb Haemost. 94: Bircher A.J., Itin P.H., Tsakiris D.A. et al Delayed hypersensitivity to one low-molecularweight heparin with tolerance of otherlow-molecular-weight heparins. Br J Dermatol. 132(3): Bircher A.J., Harr T., Hohenstein L. et al Hypersensitivity reactions to anticoagulant drugs: diagnosis and management options. Allergy. 61(12): Brockow K., Romano A., Blanca M. et al General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy. 57(1): Brockow K., Garvey L.H., Aberer W. et al Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy. 68(6): doi: /all Caballero M.R., Fernandez-Benitez M Allergy to heparin: a new in vitro diagnostic technique. Allergol Immunopathol. 31: Canti V., Yacoub M.R., Della-Torre E. et al Hypersensitivity reactions to low molecular weight heparin in a pregnant women. Current Allergy & Clinical Immunology March. 28 (1). Cesana P., Scherer K., Bircher A.J Immediate Type Hypersensitivity to Heparins: Two Case Reports and a Review of the Literature. Int Arch Allergy Immunol. 171(3-4): doi: /

10 Page 9 of 12 Canadian Journal of Physiology and Pharmacology González P., de la Sen M.L., Venegas I. et al Immediate hypersensitivity to heparins: a cross- reactivity study. J Investig Allergol clin Immunol. 24: Gonzalez-Delgado P., Fernandez J Hypersensitivity reactions to heparins. Curr Opin Allergy Clin Immunol. 16(4): doi: /ACI Grassegger A., Fritsch P., Reider N Delayed-type hypersensitivity and crossreactivity to heparins and danaparoid: a prospective study. Dermatol Surg. 27(1): Harr T., Scherer K., Tsakiris D.A. et al Immediate hypersensitivity to low molecular weight heparins and tolerance of unfractioned heparin and fondaparinux. Allergy. 61: Kavut A.B., Koca E Successful desensitization with un-fractionated heparin in a patient with heparin allergy and tolerance to fondaparinux. Asian Pac J Allergy Immunol. 30(2): Leguísamo S., Prados Castaño M., Piñero Saavedra M. et al Recurrent Anaphylaxis Due to Enoxaparin. J Investig Allergol Clin Immunol. 25(4): MacLaughlin E.J., Fitzpatrick K.T., Sbar E. et al Anaphylactoid reaction to enoxaparin in a patient with deep venous thrombosis. Pharmacotherapy. 22(11): Palacios Colom L., Alcántara Villar M., Luis Anguita Carazo J. et al Delayed-type hypersensitivity to heparins: different patterns of cross-reactivity. Contact Dermatitis. 59(6): doi: /j x. Parekh K., Burkhart H.M., Hatab A. et al Heparin allergy: successful desensitization for cardiopulmonary bypass. J Thorac Cardiovasc Surg. 130(5): Schindewolf M., Schwaner S., Wolter M. et al Incidence and causes of heparin-induced skin lesions. CMAJ. 181(8): doi: /cmaj

11 Page 10 of 12 Schindewolf M., Gobst C., Kroll H. et al High incidence of heparin-induced allergic delayedtype hypersensitivity reactions in pregnancy. J Allergy Clin Immunol. 132(1): doi: /j.jaci Weberschock T., Meister A.C., Bohrt K. et al The risk for crossreactions after a cutaneous delayed-type hypersensitivity reaction to heparin preparations is independent of their molecular weight: a systematic review. Contact Dermatitis. 65(4): doi: /j x.

12 Page 11 of 12 Canadian Journal of Physiology and Pharmacology Table 1. Summary of results of skin and challenge tests Patient Type of reaction Culprit drug(s) Case No 1 DHR nadroparin Case No 2 DHR enoxaparin nadroparin Case No 3 IHR nadroparin Tested drug Active substance (solution concentration) Dalteparin (2500 IU/0.2 ml) Enoxaparin (2000 IU/0.2 ml) Nadroparin (2850 IU/0.3 ml) Dalteparin (2500 IU/0.2 ml) Enoxaparin (2000 IU/0.2 ml) Nadroparin (2850 IU/0.3 ml) Dalteparin (2500 IU/0.2 ml) Enoxaparin (2000 IU/0.2 ml) Nadroparin (2850 IU/0.3 ml) nd: not done, sc: subcutaneously Skin prick test (1:1); readings Intradermal test (1:10); immediate reading Intradermal test (1:10); delayed reading Negative Positive Negative nd Challenge test (1:1) (volume administered) Negative Negative Negative Negative (0.1 ml sc) Negative Positive Negative nd Negative Negative Negative Negative (0.1 ml sc) Negative Negative Positive nd Negative Positive Negative nd Negative Positive nd nd Negative Positive nd nd Negative Positive nd nd

13 Page 12 of 12 Table 2. Results of cross-reactivity to other LMWHs in published cases of proven immediate-type hypersensitivity to a LMWH Case No Culprit Drug (s) Tested LMWH Skin prick test reading Intradermal tests reading Challenge test result Conclusion on crossreactivity* 1. Enoxaparin Enoxaparin Positive nd nd Cannot be Anders and Nadroparin Positive nd nd made Trautmann Dalteparin Negative nd nd Enoxaparin Enoxaparin Negative Positive nd Complete Caballero and Nadroparin Negative Positive nd Fernandez- Benitez Bemiparin Enoxaparin Negative Positive nd Complete González et al. Enoxaparin Bemiparin Negative Positive nd 2014 Dalteparin Negative Positive nd Nadroparin Negative Positive nd Tinzaparin Negative Positive nd 4. Dalteparin Dalteparin Positive Positive nd Complete Harr et al Nadroparin Positive Positive nd Enoxaparin Negative Positive nd 5. Nadroparin Nadroparin Positive nd nd Complete, Bekkenk and Dalteparin Positive nd nd but for van Zuuren Enoxaparin Negative Negative Positive tinzaparin 2005 Tinzaparin Negative Negative nd cannot be made 6. Dalteparin Dalteparin Positive nd nd Complete Cesana et al. Enoxaparin Negative Positive nd 2016 Nadropain Negative Positive nd 7. Enoxaparin Enoxaparin Negative Negative nd Complete Kavut and Koca Nadroparin Negative Negative Positive 2012 Dalteparin Negative Negative Positive Tinzaparin Negative Negative Positive 8. Nadroparin Nadroparin Negative Positive nd Complete Pp Enoxaparin Negative Positive nd Dalteparin Negative Positive nd Ref: reference; *: conclusion is based on the tested LMWHs, nd: not done; Pp: present publication Ref