Heparin allergy T88.7

Late type allergy (type IV) as a frequent and clinically relevant problem or very rarely IgE-mediated immediate type allergy (type I) to heparins.

In a meta-analysis, unfractionated heparin was found to be the main trigger in half of the cases, while low-molecular-weight heparins were found in the other half. Heparinoids only rarely have a sensitizing effect. Cross-reactions occur more frequently after initial administration of heparins than after initial treatment with low-molecular-weight heparins.

Furthermore, obesity and long therapy duration are risk factors for a heparin allergy.

In most cases, late type sensitisation is present after subcutaneous injection of heparin. Immediate type sensitization is less common.

The clinical picture depends on the type of sensitization present.

• 5-10 cm large, roundish, sharply defined, highly itchy dermatitic, also vesicular plaques at the subcutaneous injection sites. Already sensitized patients react to a further subcutaneous injection of heparin after a few (6-12) hours, more rarely only after 24-48 hours with a new local dermatitic reaction.
• Patients with dermatitic heparin allergy at the injection sites generally tolerate intravenous heparin administration (Trautmann A 2018). This allergological characteristic is called compartment allergy.
• In isolated cases, dermatitic scattering reactions (late-type allergy) may occur. More rare are generalized maculo-papular exanthema (e.g. when heparins continue to be injected despite a local dermatitic reaction).
• Urticaria, anaphylaxis, as an expression of an IgE-mediated immediate type allergy are very rare (only few publications are known)!
• DD: Of differential diagnostic importance is the rare heparin-induced thrombocytopenia (heparin necrosis) caused by microvascular skin infiltrates with lightning-figure skin necrosis.

• Intracutaneous test:
• Dilution of the injection solutions (10%) in NaCl solution 0.9%.
• Testing on the volar forearm
• Readings after 20 minutes, 24, 72 and 96 hours
• Immediate type reactions (after 20 minutes) in the intradermal test (approx. 10% of all tests) are almost always a consequence of the histamine-liberating properties of the heparins and not a symptom of an IgE-mediated allergy.
• Abrasion epicutaneous test:
• Injection solutions undiluted
• Test on the back after previous, standardised adhesive tape tear-offs
• Readings after 24, 72 and 96 hours.
• Subcutaneous provocation/exposure:
• Only after negative results of skin tests for the respective preparation!
• Outpatient injection of a therapeutic dosage
• Readings after 24, 72, 96 and 168 hours.
• Intravenous provocation:
• There should be an interval of at least 6 weeks between positive skin tests or subcutaneous provocation tests and an intravenous provocation!
• Under stationary conditions standardised with heparin sodium 5000 ratiopharm® solution (5,000 IU heparin sodium/0.2 ml)
• Day 1: 2,500 IU i.v. bolus
• Day 2: 2,500 IU i.v. in a bolus, then 7,500 IU over 6 h using a perfusor.

Notice! The subcutaneous provocation or exposure test is the most reliable method for making a diagnosis or identifying replacement preparations.

In a type II reaction, the most important differential diagnosis (in 1-4% of patients) is heparin-induced thrombocytopenia (HIT; characteristic drop in platelet numbers by more than 50% or less than 100,000/μl; "paradoxical" venous and arterial thromboembolic complications.

Skin symptoms (rather rarely occurring) are lightning-figure skin necroses (heparin necrosis) in skin areas with pronounced subcutaneous fatty tissue, such as mammae, abdomen, buttocks and thighs; latency period at first exposure 5-14 days, after second exposure 3-5 days).

Alternative preparations: Hirudin/lepirudin (direct thrombin inhibitors) are polypeptides/proteins and therefore have a fundamentally different chemical structure compared to heparin. They have favourable pharmacological properties similar to heparin (short half-life and therefore good controllability) and are therefore also suitable alternative preparations for subcutaneous application. They are regarded as a safe therapeutic alternative; allergy diagnostics regarding the tolerance of these polypeptides is not considered necessary.

Despite late-type allergy to subcutaneous injections, patients generally tolerate intravenous heparin therapy. If anticoagulation is urgently required, heparin can also be administered intravenously without prior testing.

• A 56-year-old female patient was first treated with Certoparin 8 years ago. At and far beyond the injection sites, itchy eczematous foci developed after a few weeks. The therapy was then terminated. No further allergological diagnosis.
• Two months later, a postoperative thrombosis prophylaxis was performed. After the medical history became known (allergic reaction to Certoparin), an alternative therapy with heparin was performed. After 3 injections (7,500 I.E. Heparin s.c.), flat, itchy redness developed at the injection sites; therapy was discontinued. Despite interruption of therapy, large, itchy, vesicular eczema foci developed from the erythema, which healed after 5 weeks with marked lesional hyperpigmentation.
• Allergological tests: In the IC-test: pronounced eczematous allergological test: positive reactions to Certoparin, Enoxaparin, Heparin, Tinzaparin. Fondaparinux and pentosan polysulfate showed no reaction.
• In a subsequent provocation test Fondaparinux could be determined as an alternative preparation.

1. Bircher AJ (1993) Late type allergic reactions to heparins. Allergology 16:268-274
2. Bircher AJ et al (2006) Hypersensitivity reactions to anticoagulant drugs: diagnosis and management options. Allergy 61: 1432-1440
3. Plancherel P (1953) Clinical and coagulation-physiological studies on a new heparin depot preparation. Z Clin Med 150: 213-259
4. Thoms K et al (2011) Late type heparin allergy: Too often undiagnosed? Abstract CD 46th DDG meeting FV02/04
5. Trautmann A et al. (1997) Late type allergy to heparin: Clinical - Diagnostics - Alternative drugs. Z Hautkr 72:447-450
6. Trautmann A et al (1998) Intravenous challenge with heparins in patients with delayed-type skin reactions after subcutaneous administration of the drug. Contact dermatitis 39:43-44
7. Trautmann A (2006) Heparin allergy: Late type allergy to subcutaneous heparin injection. Allergo J 15: 501-506
8. Trautmann A (2006) Allergy to Heparin s.c. What are the alternatives to thrombosis prophylaxis? dermatology 22:311, 314, 316-317
9. Trautmann A (2018) Heparin allergies - recommendations for diagnostics and patient management... Allergo J Int 27: 122-125
10. Weberschock T et al (2010) The risk of cross-reactions in type IV allergies to s.c. Heparin preparations: A systematic review. Abstract CD 46 DDG meeting: P02/01.