Hypersensitivity reactions
UFH may induce all types of DHRs, mostly type IV and type II (188). Cutaneous NIHRs to subcutaneous heparin occur at the injection site as itchy erythematous or eczematous plaques usually on the 7th-10th day of treatment; although they can appear on the 1-3thday in case of antecedent sensitization (189). Risk factors for NIHRs to heparin are obesity, female gender, old age, pregnancy, and repeated exposures (190,191). If the treatment is continued regardless of a local reaction, the patient may develop generalized eczema or exanthem (192,193). Patients with a NIHR to UFH or LMWH at injection site usually tolerate intravenous administration of UFH (189). Cross-reactivity among LMWHs has been reported in NIHRs (194). However, fondaparinux is generally well-tolerated in patients who react to LMWHs (191). Heparin may induce DRESS (195) and SJS (196).
Immune-mediated heparin-induced thrombocytopenia (HIT) is induced by IgG antibodies against complex of heparin and platelet-factor 4 tetramers (197). HIT manifests as a more than 50% decrease in the platelet count in 5 to 10 days after the onset of treatment (198). The risk of HIT is increased exclusively with UFH (199). Treatment includes the discontinuation of heparin and the introduction of an alternative anticoagulant such as argatroban, fondaparinux, danaparoid, or bivalirudin (198).
The IgE-mediated reactions to heparin manifesting as urticaria, angioedema, and anaphylaxis are rare (194,200,201). Positive STs with UFH and LMWHs have been reported (194,200,201,202). Cross-reactivity in IHRs has been reported between UFH and LMWH and among LMWHs (202).
For IHRs with heparins, diagnostic approach primarily consists of SPTs and IDTs (17). The results of BAT with UFH and LMWH are controversial (201,203,204). Heparin itself may cause a release of histamine, leading to a false positive ST. Further serial dilutions of heparin (1:100, 1:1.000, 1:10.000) might be needed (201). IDTs and PTs with the culprit and alternative heparin are performed in NIHRs (205). PTs, with tape stripping, are less sensitive but may be positive (188).
DPT is considered when the diagnosis is obscure, tissue pathology is unavailable, or an alternative anticoagulant needs to be determined (206). Subcutaneous DPTs with UFC and LMWHs are performed with increasing doses reaching up to a daily dose on the first day, then are evaluated on three consecutive days and day 7 in case of NIHRs. Intravenous DPTs with UFC may also be necessary to prove tolerance for emergency situations both for IHRs and NIHRs (188,189). A standard protocol for UFH desensitization has not been established yet and published as case reports (207,208).