Heparin allergy T88.7

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

Allergic heparin hypersensitivity; Heparin hypersensitivity

History
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Plancherel, 1952

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

Etiopathogenesis
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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.

Clinical features
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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.

Laboratory
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Has no significance or is not available.

Diagnosis
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  • 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.

Differential diagnosis
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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).

Therapy
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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.

Tables
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Position

Substance name

Concentration

Reading time

24h

72h

96h

1

Heparin (Heparin-Na-5000-ratiopharm®)

pure

2

Nadroparin (Fraxiparin® 0.3)

pure

3

Dalteparin (Fragmin® P)

pure

4

enoxaparin (Clexane® 60 mg)

pure

5

Danaparoid (Orgaran®)

pure

6

Pentosan polysulfate (Fibrezym®)

pure

7 Fondaparinux (Arixtra® 2.5 mg) pure

8

heparin compound suspected of being a medical history

pure


Position

Substance name

Vehicle

Concentration

Reading time

20min

24h

72h

96h

1

Histamine

pure

2

Control

NaCl

pure

3

Heparin (Heparin-Na-5000-ratiopharm®)

NaCl

10%

4

Nadroparin (Fraxiparin® 0.3)

NaCl

10%

5

Dalteparin (Fragmin® P)

NaCl

10%

6

enoxaparin (Clexane® 60 mg)

NaCl

10%

7

Danaparoid (Orgaran®)

NaCl

10%

8

Pentosan polysulfate (Fibrezym®)

NaCl

10%

9 Fondaparinux (Arixtra® 2.5 mg) NaCl 10%

10

heparin compound suspected of being a medical history

NaCl

10%

Note(s)
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In the case of HIT, a general ban on heparin applies; alternatively, Danaparoid (Orgaran®) or Hirudine [ Lepirudin] are recommended for anticoagulation.

Case report(s)
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  • 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.

Literature
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  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.

Disclaimer

Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

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Last updated on: 29.10.2020