Indian Journal of Dermatology
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E-CASE REPORT
Year : 2014  |  Volume : 59  |  Issue : 4  |  Page : 423
Bullous hemorrhagic dermatosis: A case report


Department of Dermatology, Sri Dharmasthala Manjunatheshwara College of Medical Sciences and Hospital, Sattur, Dharwad, India

Date of Web Publication27-Jun-2014

Correspondence Address:
Dr. Kikkeri Narayanasetty Naveen
622, Manya Towers Sdmcmsh Sattur, Dharwad
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.135544

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   Abstract 

We present a case of hemorrhagic bullous dermatosis occurring in areas distant from the site of injection of enoxaparin. A 88 year old woman was admitted for inter trochantric fracture. She was put enoxaparin 60mg subcutaneous 12 hrly for deep vein thrombosis. After 5 days she developed huge hemorrhagic bulla on left leg and multiple hemorrhagic bullae at other sites distant from injected site. A diagnosis of Bullous hemorrhagic dermatoses due to enoxaparin was made. Enoxaparin was stopped and started on oral heparin. Lesions started to regress. Only 9 similar cases have been reported throughout world and none from India.


Keywords: Bullous hemorrhagic dermatoses, enoxaparin, heparin


How to cite this article:
Naveen KN, Rai V. Bullous hemorrhagic dermatosis: A case report. Indian J Dermatol 2014;59:423

How to cite this URL:
Naveen KN, Rai V. Bullous hemorrhagic dermatosis: A case report. Indian J Dermatol [serial online] 2014 [cited 2020 Jan 24];59:423. Available from: http://www.e-ijd.org/text.asp?2014/59/4/423/135544

What was known?
Enoxaparin can cause bleeding as side effect.



   Introduction Top


Low molecular weight heparin (LMWH) preparations were first approved for the prevention of venous thromboembolism. They are also effective in the treatment of venous thrombosis, pulmonary embolism, and unstable angina. Many LMWH preparations are available such as, Enoxaparin, Dalteparin, Tinzaparin, Ardeparin, Nadroparin, and Reviparin, which differ considerably in composition. [1] The most common adverse skin effects with these anticoagulants are ecchymoses, skin necrosis, urticaria, angioedema, and eczema. [2]

We present a case of hemorrhagic bullous dermatosis occurring in areas distant from the site of the injection of Enoxaparin. Only nine similar cases have been reported throughout the world and none from India.


   Case Report Top


An 88-year old woman with a history of diabetes mellitus and hypertension was admitted for intertrochanteric fracture of right hip 4 months back. Patient was treated conservatively with skeletal traction, diclofenac, tramadol, and ceftazidime, and was advised bed rest. She was recently admitted under orthopedic department with swelling of both lower limbs of 4 days and was started on oral Amoxycillin with clavulinic acid, multivitamin syrup, and oral paracetamol. She was referred to a surgeon and Doppler was done that showed features suggesting deep vein thrombosis of the right lower limb. Patient was started on Enoxaparin 60 mg subcutaneously every 12 h. 5 days later she developed asymptomatic hemorrhagic bulla over the medial border of the left foot near the ankle joint. Physical examination revealed a solitary hemorrhagic bulla over the dorsum of the left foot along the ankle joint measuring 7 × 5 cm [Figure 1]. Similar bullae were found on the right shin [Figure 2] and medial side of the left arm. There was no bulla visible over the injection site. The patient did not report bleeding from any other area of the body. The bulla was drained under aseptic conditions and dressing done.
Figure 1: Tense hemorrhagic bulla on the medial side of left leg above ankle

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Figure 2: Hemorrhagic bulla on an erythematous base on the right leg

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Laboratory tests were within the normal ranges for platelet count and coagulation studies (bleeding time (BT), clotting time (CT), prothrombin time (PT), and international normalized ratio (INR)). Peripheral smear revealed normocytic, normochromic anemia with hemoglobin 9.2 mg/dL. The patient did not give consent for the biopsy; hence, biopsy was not done.

Enoxaparin was stopped and oral warfarin 2 mg on alternate days was given to the patient for 3 days, later increased to 5 mg on alternate days. The bulla resolved within 2 days of stopping enoxaparin [Figure 3]. On discharge patient was asked to continue oral warfarin 2 mg for alternate days.
Figure 3: Lesion after 2 days after draining bulla

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   Discussion Top


Low molecular weight heparins are isolated from standard heparin by gel filtration chromatography, precipitation with ethanol, or partial depolymerization with nitrous acid and other chemical or enzymatic reagents. Enoxaparin is an LMWH obtained by depolymerization of standard heparin. It produces an anticoagulant effect mainly through inhibition of the Xa factor. Though bleeding is the most common side effect of enoxaparin, it is less compared to standard heparin. [1]

In 2006, Perrinaud et al. for the first time described three patients in whom bullous hemorrhagic dermatosis developed without thrombosis of dermal vessels at sites distant from subcutaneous injections of heparin. [3] The first case was a 75-year-old man, who developed approximately 50 hemorrhagic bullae, 5 days after starting dalteparin. Later they switched over to oral anticoagulants, but the patient died, possibly due to antivitamin k over dosage. Second case was of an 82-year-old woman, who developed tense hemorrhagic bullae, 6 days after starting tinzaparin. Tinzaparin was discontinued 2 days after the development of lesion and they resolved completely after 10 days. Intradermal tests with tinzaparin performed 1 month later were found to be normal. Third case was of a 64-year-old man, who developed 10 hemorrhagic bullae, 21 days after starting heparin calcium. The skin lesions resolved despite continuation of treatment with heparin. [3]

Later, in 2009, Beltraminelli et al.[4] and Gonzales et al.[5] reported a total of three cases similar to those described by Perrinaud et al. [3] and they were associated with the administration of enoxaparin sodium. In the same year, Thuillier et al.[6] reported a case of 51-year-old male who was started on subcutaneous enoxaparin sodium. Few days later it was replaced by tinzaparin sodium. After 2 days they noticed eczema at the injected site and hemorrhagic bullous dermatosis on the abdominal wall. Skin lesions disappeared ten days after discontinuation of LMWH. Patch tests and intradermal tests were negative.

In 2012, Villanueva et al.[2] reported two cases of hemorrhagic bullous dermatosis after 8 and 10 days of starting on enoxaparin. The lesions resolved without sequelae in 2 to 3 weeks in spite of continuing with treatment.

Total nine cases have been reported in the literature. Time for the onset of the lesions after the administration of the drug varied from 2 to 21 days in the above reports. In our case, the time for onset was 5 days.

The affected age group was in the range of 60-90 years, except one case reported by Thuillier et al. where the patient was 51-year old. In this case, the age of the patient was 88 years.

Routine coagulation studies were normal in the majority of the cases similar to our case, except cases reported by Beltraminelli et al.[4] and Gonzales et al. [5]

There are no clear guidelines regarding the management of the lesions. Perrinaud et al. observed that the lesions resolved completely in one patient despite continuation of treatment with heparin. Villanueva et al. also preferred to continue treatment with enoxaparin and noticed complete resolution of lesions at the end of 3 weeks. We substituted enoxaparin with oral warfarin and lesions started to regress.

Enoxaparin has been implicated as the causative drug in seven out of ten cases including the present case. In remaining three cases, Dalteparin, Tinzaparin, and Heparin have been implicated. The principal advantage of LMWH over standard heparin is a more predictable pharmacokinetic profile, which allows weight-adjusted subcutaneous administration without laboratory monitoring. Thus, therapy of many patients can be provided in the outpatient setting. Other advantages of LMWH include a lower incidence of heparin-induced thrombocytopenia and possibly lower risks of bleeding and osteopenia. Hence, enoxaparin is preferred over heparin. [1]

We conclude by stating that we report a case of hemorrhagic bullous dermatosis at a site distant from the injection site of Enoxaparin. This is the first case reported in India. It is a self-limiting condition, even without discontinuation of the treatment, could mean that probably it is under diagnosed phenomenon or one that is under reported in the literature. Enoxaparin is widely used nowadays because of its ease in administration and relatively less side effects. Dermatologists are likely to encounter these benign, self-limiting lesions in their practice, and should be aware of its favorable clinical course.

 
   References Top

1.Majerus PW, Tollefsen DM. Blood coagulation and anticoagulant, thrombolytic, and antiplatelet drugs. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman and gilman's the pharmacological basis of therapeutics. 11 th ed. New York: Mcgraw-Hill; 2006. p. 1470-5.  Back to cited text no. 1
    
2.Villanueva CA, Najera L, Espinosa P, Borbujo J. Bullous Hemorrhagic Dermatosis at Distant Sites: A Report of 2 New Cases Due to Enoxaparin Injection and a Review of the Literature. Actas Dermosifiliogr 2012;103:816-9.  Back to cited text no. 2
    
3.Perrinaud A, Jacobi D, Machet MC, Grodet C, Gruel Y, Machet Bullous L. Hemorrhagic dermatosis occurring at sites distant from subcutaneous injections of heparin: Three cases. J Am Acad Dermatol 2006;54(Suppl 2):S5-7.  Back to cited text no. 3
    
4.Beltraminelli H, Itin P, Cerroni L. Intraepidermal bullous haemorrhage during anticoagulation with low-molecular-weight heparin; two cases. Br J Dermatol 2009;161:191-3.  Back to cited text no. 4
    
5.Gonzales UP, Scott GA, Briones AJ, Pentland AP. Remote hemorrhagic bullae occurring in a patient treated with subcutaneous heparin. Arch Dermatol 2009;145:604-5.  Back to cited text no. 5
    
6.Thuillier D, Chaby G, Dadban A, Dascotte E, Miquel-Christophe D, Andrejak M, et al. Low molecular weight heparin induced bullous haemorrhagic dermatosis associated with cell mediated hypersensitivity. Ann Dermatol Venereol 2009;136:706-70.  Back to cited text no. 6
    

What is new?
Bullous hemorrhagic dermatoses due to enoxaparin at a site distant from injected site.


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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