PRACTICE | CASES CPD

Probable fondaparinux-associated bullous hemorrhagic dermatosis

Catherine Anne Lovatt MD, Wen Qing Wendy Ye MD MSc, Haroon Yousuf MD MHSc n Cite as: CMAJ 2021 May 31;193:E801-4. doi: 10.1503/cmaj.202747

90-year-old woman was admitted to a tertiary hospital with hypoxia secondary to pulmonary edema and KEY POINTS on­going antibiotic therapy following an infected hip • Bullous hemorrhagic dermatosis is an uncommon nonimmune prosthesis.A The patient’s medical history included heparin- adverse drug reaction to heparin-based anticoagulants induced thrombocytopenia following administration of dalte­ including unfractionated heparin, low-molecular-weight parin, atrial fibrillation (CHADS2 score of 3) and lower gastrointes- heparin and fondaparinux that typically occurs within 7 days of tinal bleeding related to diverticular disease. The patient did not drug exposure. report any skin allergies. On admission, she was 4 weeks post- • The reaction is more common in older adults, and lesions are usually found on the extremities. removal of right hip hardware, débridement and revision to a cemented right hip hemiarthroplasty for methicillin-sensitive • There are typically no changes to coagulation tests such as the international normalized ratio, partial thromboplastin time or Staphylococcus aureus infection, and was completing a 6-week the prothrombin time. course of cephalexin and rifampin. She had previously taken • Bullous hemorrhagic dermatosis is self-resolving, although apixaban for stroke prophylaxis but, before admission, her apixa- careful monitoring of bleeding, and supportive management ban was switched to warfarin because of its interaction with such as wound care and transfusion of blood products, may rifampin. However, given the interaction between warfarin and be required. rifampin and her complex history of thrombosis, we consulted the thrombosis service regarding management of the patient’s anticoagulation. We then began daily fondaparinux injections punch biopsy from the left arm taken on day 10 showed only into her abdomen while continuing rifampin. The patient’s dermal solar elastosis and atrophic epidermis, which was not ­dyspnea resolved with intravenous furosemide. consistent with vasculitis. In consultation with the rheumatol- On the fourth day of fondaparinux, the patient developed deep ogy service, we decided that the extractable antibody panel purple hemorrhagic lesions not associated with trauma — which result was likely spurious. were neither painful nor pruritic — and bullae on her left forearm We diagnosed fondaparinux-induced bullous hemorrhagic (Figure 1). These progressed in size and number over the next dermatosis. We clearly documented possible life-threatening 2 days, eventually affecting her right arm but remained isolated to reactions to all heparin-related products on her medical chart, the upper extremities. Mucosal membranes were not involved. The and discussed this with the patient and her family. left epicondylar bullae ruptured on day 6 of fondaparinux resulting On the advice of the infectious diseases team, we discontin- in substantial hemorrhage. While the patient’s hemoglobin ued rifampin and restarted the patient on low-dose apixaban for dropped from 91 (normal 130–180) g/L on day 4 of fondaparinux ongoing stroke prophylaxis. The hemorrhagic bullae completely therapy to 70 g/L on day 6, her coagulation parameters were in the resolved after we discontinued fondaparinux, with desiccation of upper normal range: international normalized ratio (INR) 1.2 (nor- the bullae and involution of the skin discoloration on day 23 mal 0.8–1.2), prothrombin time (PT) 14.9 (normal 11–15) seconds, (Figure 2). and partial thromboplastin time 41 (normal 22–35) seconds. We This hospital admission profoundly affected our patient’s did not identify any other source of bleeding or hemolysis. We quality of life. Owing to deconditioning and resultant frailty she gave the patient 4 units of packed red blood cells over 3 days, and ultimately applied to long-term care. discontinued fondaparinux on day 7 because of ongoing bleeding. We dressed her skin lesions with tranexamic acid–soaked com- Discussion pression dressings. A thorough medication review did not show other potential causes of hemorrhagic bullae. Epidemiology and differential diagnosis Rheumatologic panels on day 6 showed a positive extract- Bullous hemorrhagic dermatosis is an uncommon, non-immune- able antibody panel with positive anti-Ro/SSA52 at 4.1 (normal mediated, systemic adverse effect of heparin-based anticoagu- < 1.0). We suspected vasculitis-related hemorrhagic bullae, but a lants. It has been most commonly reported with enoxaparin,

© 2021 CMA Joule Inc. or its licensors CMAJ | MAY 31, 2021 | VOLUME 193 | ISSUE 22 E801 PRACTICE reviewed journals. reported, andonly97cases havebeendescribedinpeer- E802 exposure. and typically appears after 7 days (range 3–270 d) of medication Figure 2:Resolutionofbulloushemorrhagic dermatosisonthepatient’sleftarmday23. fondaparinux administration. Figure 1:Photographsofbulloushemorrhagicdermatosislesionsontheleftarmandhanda90-year-oldwoman,day6(A)10 (B) of 1,2 Bullous hemorrhagic dermatosis is likely under- 1,3–6 Thecondition has beenreportedprevi- CMAJ | MAY 31,2021 | VOLUME 193 bullous hemorrhagic dermatosis,Russoand colleaguesfound direct oralanticoagulants.Ina summaryof91reportedcases warfarin. ously inrelationtoacombination offonda­ 7,8 Therehavebeennoreported casesassociatedwith | ISSUE 22 parinux and PRACTICE E803

Given 1 5,10 Given the severity of Given the severity of 1 Leukocytoclastic vasculitis Leukocytoclastic bullous pemphigoid Atypical pemphigoid bullous Drug-induced Epidermolysis bullosa acquisita vulgaris Pemphigus pemphigus Paraneoplastic gangrenous Bullous pyoderma purpura Henoch–Schönlein tarda cutanea Porphyria Hemophilia skin necrosis Heparin-induced necrosis Warfarin Hemorrhagic spider bites fasciitis Necrotizing Bullous hemorrhagic cellulitis virus Varicella-zoster blood blisters Friction ISSUE 22 ISSUE | Table 1: Differential diagnosis of hemorrhagic bullae of hemorrhagic diagnosis 1: Differential Table Immune-mediated Blood-based Drug- or toxin-mediated Infectious Mechanical that bullous hemorrhagic dermatosis tends to be self-limited, that bullous hemorrhagic dermatosis tends to be self-limited, some experts have argued that stopping the offending agent 23% of cases to resolution. About difference in time makes little resolved even though the suspected medication causing bullous a on resolved 14.3% and continued, was dermatosis hemorrhagic lowered dose or change in anticoagulant. Conclusion self- nonimmune, rare a is dermatosis hemorrhagic Bullous resolving drug reaction that occurs with heparin-based anti­ coagulants. This reaction is more common in older adults, and can result in hemodynamic instability requiring transfusion. The risks and benefits of ongoing anticoagulation must be evaluated on an individual basis. Management to an alternative Stopping the offending agent or transitioning treatment strat­ anticoagulation agent are the most common cases. reported egies, and have been used in about 60% of our patient’s case, which included hemodynamic instability our patient’s case, which included hemodynamic instability anti- all discontinuing that considered we transfusion, requiring coagulation agents was prudent. We have reported this case to the Canada Vigilance Program. thrombocytopenia and does not confer susceptibility to other susceptibility to other thrombocytopenia and does not confer no reported cases of immune reactions. There have been with patients in thromboembolism arterial or venous increased central to the diagno- bullous hemorrhagic dermatosis, which is Given that bullous sis of heparin-induced thrombocytopenia. the patient’s hemorrhagic dermatosis is not immune mediated, and subsequent history of heparin-induced thrombocytopenia with dermatosis hemorrhagic bullous of development fondaparinux are likely coincidental. VOLUME 193 VOLUME | ­ ­ MAY 31, 2021 MAY | Heparin-induced Heparin-induced Case reports have Case reports have This is a different different a is This 1 1 13 CMAJ 7,10 12 Given the advanced average age of Given the advanced average age of 1 In most cases, bullous hemorrhagic bullous hemorrhagic In most cases, 1,4 Four deaths have been associated with the associated with the Four deaths have been 9 There was also no evidence of skin or or There was also no evidence of skin hemorrhagic dermatosis according to the the hemorrhagic dermatosis according to 11 Organization–The Uppsala Monitoring Centre Centre Organization–The Uppsala Monitoring 1 Hemorrhagic bullae related to an acquired hemophilia hemophilia acquired an to related bullae Hemorrhagic The range of differential diagnoses for hemorrhagic bullae diagnoses for hemorrhagic bullae The range of differential Our patient may have been predisposed to bullous hemor- eters such as international normalized ratio or partial throm- eters such as international normalized boplastin time. (e.g., acquired factor VIII deficiency) are also immune related, also immune related, (e.g., acquired factor VIII deficiency) are param anticoagulation change to expected be would and is broad (Table 1). For our patient, the differential included For our patient, the differential included is broad (Table 1). - necrosis, vasculitis-related hemor warfarin-induced skin bullous pemphigoid, rhagic bullae, cephalexin-induced blisters, acquired hemophilia and bullous mechanical friction The onset of warfarin-induced skin hemorrhagic cellulitis. within a few days of drug exposure and necrosis is typically subcutaneous fat, including breast and occurs in areas with in fit the onset or distribution of lesions thighs. This did not many forms of drug- our patient. Bullous pemphigoid and immune-mediated are reactions cutaneous mediated was which infiltration, eosinophil with associated responses not evident on our patient’s skin biopsy. described a possible association between bullous hemorrhagic described a possible association between bullous hemorrhagic dermatosis and eczematous reactions at injection sites, sug- reaction. hypersensitivity IV type a gesting condition. immune mechanism from that involved in heparin-induced immune mechanism from that involved in heparin-induced

Pathophysiology dermatosis has The pathophysiology of bullous hemorrhagic tend to show intra­ not been fully elucidated. Skin biopsies of immune cells or epidermal hemorrhage in the absence markers of inflammation. that lesions are not typically painful, pruritic or associated with with associated pruritic or painful, not typically are that lesions is most often lesion distribution symptoms; and other systemic the being affected sites primary with sites, injection to distant the of involvement rare with torso, the by followed extremities, mucosal membranes. systemic infection. Given the punch biopsy pathology report, pathology report, ­systemic infection. Given the punch biopsy fondaparinux, self- the time correlation with the onset of plausible alternative resolution of the lesions and a lack of case of fondaparinux- explanations, we diagnosed a probable induced bullous ­ World Health ­ causality assessment system. dermatosis is self-resolving, with time to resolution within an an within resolution to time with self-resolving, is ­dermatosis average of 13 days. thrombocytopenia is an immunoglobulin G antibody–mediated thrombocytopenia is an immunoglobulin G antibody–mediated adverse drug reaction to heparin products. patients with bullous hemorrhagic dermatosis, some have patients with bullous hemorrhagic dermatosis, some have ­theorized a relationship to epidermal-dermal fragility. This would be consistent with our patient’s case, given the atrophic epidermis described in her skin biopsy. She had crepe skin consistent for her advanced age but no prior noted skin lesions or breakdown. of risk increased of combination a of because dermatosis rhagic skin necrosis from heparin-induced thrombocytopenia 6 months previously, delayed skin healing and increased skin comorbidities. and age to owing fragility PRACTICE E804 13. 12. 11. 10. References 5. 6. 9. 8. 7. 4. 3. 2. 1.

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| VOLUME 193 Correspondence to:HaroonYousuf,[email protected] licenses/by-nc-nd/4.0/ cations or adaptations are made. See: https://creativecommons.org/ use isnoncommercial(i.e.,researchoreducationaluse),andnomodifi- medium, provided that the original publication is properly cited, the ND 4.0) licence, which permits use, distribution and reproduction in any dance withthetermsofCreativeCommonsAttribution(CCBY-NC- Content licence: published andagreedtobeaccountableforallaspectsofthework. important intellectualcontent,gavefinalapprovaloftheversiontobe design ofthework,draftedmanuscript,reviseditcriticallyfor Contributors: (Yousuf), Hamilton,Ont. Health Sciences,McMasterUniversity;HamiltonSciences Affiliations: DepartmentofMedicine(Lovatt,Ye,Yousuf),Faculty The authorshaveobtainedpatientconsent. This articlehasbeenpeerreviewed. Competing interests:Nonedeclared. necessity. Seeinformationforauthorsatwww.cmaj.ca. encouraged. Consentfrompatientsfor publication of their storyis a ferential diagnosis,clinicalfeaturesordiagnosticapproach)are lows (1000wordsmaximum).Visualelements(e.g.,tablesofthedif- words maximum), and a discussionoftheunderlying condition fol- common problems.Articlesstartwithacasepresentation(500 important rareconditions,andunusualpresentationsof practical lessons.Preferenceisgiventocommonpresentationsof The sectionCasespresentsbriefcasereportsthatconveyclear, | ISSUE 22 All of the authors contributed to the conception and This is an Open Access article distributed in accor -