Clinical Features, Diagnosis, Treatment, and Prognosis of Heparin-Induced Bullous Hemorrhagic Dermatosis

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Introduction
Heparin is the most widely used anticoagulant for the treatment and prevention of thromboembolic diseases, including acute coronary syndrome, deep vein thrombosis, pulmonary thromboembolism, and autoimmune diseases, which are associated with an increased risk of thrombosis [1].Te types of heparin are divided into unfractionated heparins (UFHs) and low molecular weight heparin (LMWH), which act as anticoagulants by activating antithrombin III [2].Bleeding is the most common treatment complication, and other complications include heparin-induced thrombocytopenia, liver injury, osteoporosis, and skin reactions [3].Adverse skin reactions can include erythema, urticaria, hematoma at the injection site, skin necrosis, contact dermatitis, and intradermal microvascular thrombosis [4].Bullous hemorrhagic dermatosis (BHD) is a rare and underrecognized cutaneous complication of heparin therapy that occurs in a diferent area than the injection site.Te knowledge regarding heparin-induced bullous hemorrhagic dermatosis (HBHD) is based mainly on case reports.Te clinical features, treatment, and prognosis of HBHD patients remain unclear.Here, we discuss the clinical features of HBHD to provide evidence for the rational use of heparin.

Retrieval Strategy.
We collected case reports, case series, and clinical studies of HBHD by searching the PubMed, Embase, Cochrane Library, Wanfang, China National Knowledge Infrastructure, and China Science and Technology Journal Database databases.Te retrieval period was from the establishment of the database to December 31, 2022.Te search terms included heparin, unfractionated heparins, low molecular weight heparin, enoxaparin, tinzaparin, bemiparin, dalteparin, reviparin, anticoagulants, hemorrhagic bullous dermatosis, hemorrhage, blisters, and bullae.

Inclusion and Exclusion
Criteria.HBHD-associated patients were included.Reviews, mechanistic studies, duplicates, animal studies, systematic reviews, and metaanalyses were excluded.

Data Collection.
We designed tables and extracted patient information, including nationality, sex, age, heparin type, administration regimen, medical history, concurrent medications, clinical manifestations, laboratory tests, histopathology, direct immunofuorescence, treatment, and prognosis.

Statistical Analysis.
Statistical analysis was performed using SPSS 22 software.Count data are represented by n (%), and continuous data are represented by median values (minimum and maximum).

Treatment and Prognosis.
Te treatment and prognosis of the 72 HBHD patients are summarized in Table 4. Fortyfour patients (61.1%) stopped using heparin, 20 patients (27.8%) continued to use heparin, the dose of heparin was reduced in 1 patient (1.4%), and the treatment details were not described in 7 patients (9.7%).Twenty-one patients (29.2%) switched to other anticoagulants, including oral anticoagulants (15 patients, 20.8%), fondaparinux (2 patients, 2.8%), and another LMWH (4 patients, 5.6%).Sixty-seven patients (93.1%) recovered completely, and the outcomes of 5 patients (6.9%) were not reported.Te causes of the deaths of four patients were not related to BHD.In 46 patients, the median recovery time of the skin lesions was 14 days (range: 2, 141).One patient experienced BHD again after reusing enoxaparin following improvement in the patient's BHD.

Discussion
BHD is a nonpruritic, tensive, hemorrhagic bullosa that can develop on normal skin.HBHD occurs at a distant location from the heparin injection site and usually appears 7 days 2 Dermatologic Terapy  Dermatologic Terapy 3 after heparin administration.HBHD is found mainly in the extremities, hands, and abdomen and is rarely accompanied by itching and pain.It should be noted that the oral mucosa may also be involved [5].HBHD lesions can vary in size from 1 mm to 70 mm and appear as black hemorrhagic blisters.HBHD is age independent and can occur at any age.Nearly all heparins can cause HBD, and enoxaparin is the most common cause of HBHD, which may be related to the fact that enoxaparin is the most commonly used low molecular weight heparin [6].
Male sex can be a risk factor for HBHD, and 70% of the people with HBHD are male.A higher heparin dose may not be a risk factor for HBHD.BHD occurred in patients receiving both therapeutic and prophylactic doses of heparin, with one patient receiving only one dose of enoxaparin [7].In this study, we found that 39% of the patients were also Represents the number of patients out of 72 for whom information regarding this particular parameter was provided.
It is not clear whether there is a cross-reaction between UFHs and LMWH.One patient developed BHD after enoxaparin administration, but UFHs could be used safely [12].While there may be cross-reaction between low molecular weight heparin, one patient developed BHD after using enoxaparin and one patient also developed hemorrhagic blistered skin disease after continuing to use tinzaparin [13].LMWH may also cross-react with fondaparinux.One patient developed BHD after using tinzaparin, but the patient was switched to fondaparinux after the patient developed another outbreak of BHD [14].Te cross-reaction between fondaparinux and LMWH may be a result of their identical fve-sugar sequence structures.Heparin induces the production of platelet-aggregating immunoglobulins that can lead to thrombocytopenia, skin necrosis, and thrombotic events.Obesity, diabetes, and broad-spectrum antibiotic therapy are risk factors for these complications [15].
Skin biopsies and DIFs have played an important role in distinguishing BHD from other skin lesions, such as bullous pemphigoid, bullous pemphigoid drug eruption, bullous erysipelas, and necrotizing fasciitis.Biopsy of BHD lesions reveal congested vesicles and blisters within the epidermis or intraepidermally but no vasculitis or capillary thrombosis.Approximately, 51% of the patients had no infammatory infltration in their tissue biopsies, and infltration of infammatory cells, such as lymphocytes, eosinophils, and neutrophils, were only visible in a few patients.
Te pathogenesis of HBHD has not been elucidated.Te skin lesions in this condition are far from the injection area, which suggests that the drug reaction may be a systemic rather than a local response.Heparin-induced skin injury is currently believed to involve fve major mechanisms, including delayed hypersensitivity, immune-mediated thrombocytopenia, type I anaphylaxis, skin necrosis, and impetigo [16,17].Heparin-induced bleeding tendencies can be ruled out as a cause of the BHD in these HBHD patients based on their normal coagulation function and platelet counts.Immune-mediated heparin-associated thrombocytopenia (HIT) and delayed hypersensitivity can be further ruled out by the absence of HPF4 antibodies and intraepidermal/subepidermal bulla-negative DIF test results.Te DIF in one patient showed that C3 was strongly positive at the dermoepidermal junction, possibly due to underlying bullous pemphigoid [18].Perrinaud et al. suggested that this mechanism may be due to a particular reaction, but the real cause remains unclear [19].
An optimal treatment for BHD is not available.Most patients with BHD fully recovered after heparin discontinuation.Some patients have gradually recovered from BHD despite the continuation of heparin.Te median time to resolution of bullous lesions was 2 weeks.One HBHD patient with severe hemorrhagic rupture experienced BHD recurrence after a reintroduction of enoxaparin [18].Te continued use of heparin may be a risk factor for the severity of BHD [20][21][22].Nevertheless, further research is needed to determine which conditions can still be treated with heparin and which ones that heparin needs to be discontinued.Steroids may be an option in patients with severe hemorrhagic bullous lesions [19].

Limitations
Tis study has several limitations.First, the data are based on case reports and series that contain more unknown factors than those of controlled studies.Second, not all the literature provided complete clinical data; for example, only 57 patients underwent skin biopsies.Tird, the number of included patients was small, and more studies are needed to clarify the risk factors and optimal treatment for HBHD.Finally, whether diferent types of BHD are induced by diferent heparins is important for protocol replacement.

Conclusions
In summary, HBD is a rare adverse event of heparin that is curable with either continuation or suspension of heparin therapy.Clinicians and pharmacists should inform patients Represents the number of patients out of 72 for whom information regarding this particular parameter was provided.b Median (minimum-maximum).
Dermatologic Terapy of the possible occurrence of HBHD and monitor patients carefully during heparin therapy.Te clinician should decide whether to continue with heparin or switch to oral anticoagulants based on the patient's situation.

Table 1 :
Basic characteristics of 72 patients with HBHD.

Table 2 :
Heparin administration regimen in 72 patients with HBHD.
UFH, unfractionated heparin; LMWH, low molecular weight heparin.a Represents the number of patients out of 72 for whom information regarding this particular parameter was provided.b Median (minimum-maximum).

Table 3 :
Clinical features of 72 patients with HBHD. a

Table 4 :
Treatment and prognosis of 72 patients with HBHD.