Heparin skin necrosis—an important indicator of potentially fatal heparin hypersensitivity

Skin necrosis at injection sites is a rare complication of heparin therapy. In this report, we describe only the second case of the even rarer complication of skin necrosis occurring at sites distant to those of subcutaneous heparin injections. The patient had also suffered systemic thrombotic events due to heparin-dependent platelet activation prior to the development of the skin necrosis, although these had not been recognized as such at the time. The development of heparin-induced skin necrosis should result in the immediate cessation of heparin therapy in order to prevent potentially fatal thrombotic events. This is in contrast to warfarin-induced skin necrosis, where therapy may be continued or restarted at a lower dose.     

Skin necrosis following subcutaneous heparin injection

Heparin-induced skin necrosis is a rare but serious complication of subcutaneously administered heparin. Previous reports indicate that the skin necrosis is often accompanied by thrombocytopenia and occasionally by lethal thromboembolism. It thus shows features similar to the heparin-induced thrombocytopenia (HIT) syndrome and probably represents a localized form of this condition. Caution is required in the event of skin necrosis; heparin therapy should be ceased immediately and not used again if the complications of HIT are to be avoided.     

Heparin-induced thrombocytopenia and warfarin-induced skin necrosis: case report

This paper describes a case of heparin-induced thrombocytopenia complicated by warfarin-induced skin necrosis in a 74-year old female patient hospitalized with diagnoses of a hip fracture, deep vein thrombosis and pulmonary thromboembolism. Warfarin-induced skin necrosis is a rare complication of anticoagulant therapy, with high morbidity and mortality that may be associated with heparin-induced thrombocytopenia.     

Hautnekrose als kutane Manifestation einer heparininduzierten Thrombopenie Typ?II?

Most of the rare cases of skin necrosis following heparin injections are associated with the immunologically mediated form of heparin-induced thrombocytopenia II (HIT II). We present a 62-year- old woman who developed a necrotic abdominal lesion seven days after starting daily subcutaneous injections of the low molecular heparin enoxaparin. We detected circulating antibodies against the platelet factor 4-complex but no concomitant thrombocytopenia. An isolated, antibody-mediated thrombosis of dermal vessels is the likely underlying cause of the skin necrosis in HIT II.     

Warfarin-Induced Skin Necrosis

Warfarin-induced skin necrosis is an infrequent complication occurring in individuals under warfarin treatment who have a thrombophilic history or after administration of large loading doses of warfarin particularly without simultaneous initial use of heparin. A 62-year-old lady developed skin necrosis 4 days after initiating warfarin therapy of 5 mg daily without initial co-administration of heparin. The patient had a normal clotting profile. Skin necrosis progressed to eschar formation after cessation of warfarin and heparinization stopped expanding. Warfarin was reintroduced at 2 mg daily, initially together with low molecular weight heparin. Autolytic debridement of the necrotic tissue was followed by healing of the cutaneous deficit by secondary intention. Prompt diagnosis and discontinuation of warfarin are crucial for the prognosis.     

Haut- und Schleimhautulzerationen bei heparininduzierter Thrombozytopenie (HIT) II

About 0.1-2% of patients receiving heparin develop heparin-induced thrombocytopenia type II (HIT II) which is caused by antibodies directed against heparin-platelet factor 4 (PF4) complexes. Activation of thrombocytes and endothelial cells can lead to thrombocytopenia, venous and arterial thrombosis or thromboembolic events 10-14 days after the first dose. HIT II has a high mortality rate because of pulmonary emboli, cerebrovascular accidents, myocardial and limb infarctions. A 55-year-old patient with HIT II presented with arterial and venous thromboses and a silent myocardial infarction. In addition, he showed extensive skin and mucosal necrosis, an uncommon complication. Rheologic therapy with danaparoid Natrium, alprostadil alfadex and acetylsalicylic acid in combination with percutaneous transluminal angioplasties as well as local and systemic antiinflammatory therapy prevented further progression of the disease.     

Cutaneous Reactions to Anticoagulants

Anticoagulant-induced skin reactions appear as allergic or necrotic responses to vitamin K antagonists or heparins. Cutaneous allergy has been reported with danaparoid sodium and flush reactions have been seen with hirudins. The pathogenesis of the reactions differs between drugs. Generally, they occur between days 3 to 10 after the start of treatment, but may also occur later. In patients experiencing necrosis with a vitamin K antagonist, concomitant protein C deficiency, protein S deficiency or lupus anticoagulant has been described, whereas the precise mechanism of the other reactions is unknown. In patients with allergic reactions to heparins, cutaneous tests may help to identify alternative anticoagulants. Such a test cannot be performed in patients with skin necrosis. In patients with heparin-induced skin reactions danaparoid sodium may be used after negative intracutaneous testing in some patients and a hirudin may be used without testing in all patients. Heparin-induced skin necrosis has been reported to be mediated by immunologic mechanisms and to be associated with a high frequency of heparin-induced thrombocytopenia type II. Surgical excision of the necrosis may be required. If further anticoagulation is indicated in any patient, extreme caution has to be taken when restarting oral anticoagulants. Because a large number of anticoagulants available today, safe treatment of all patients experiencing anticoagulant-induced skin reactions is feasible.     

Delayed-type hypersensitivity to heparin: diagnosis and therapeutic management

Heparin is widely used as an anticoagulant and is indicated in the prevention and treatment of thromboembolic disorders. Heparin-induced delayed-type hypersensitivity presents as eczematous lesions, either at the injection site or generally, and affects 7.5% of patients on heparin. This poses diagnostic and therapeutic issues, since an alternative anticoagulant treatment is essential and the risk of cross-reactivity may be as high as 80%, depending on the type of heparin used. If delayed-type hypersensitivity is suspected, heparin-induced thrombocytopenia must first be ruled out, and heparin should be stopped. Fondaparinux is currently the first-line alternative, with a risk of cross-reactivity estimated at only 10%. The switch from a low-molecular-weight heparin (LMWH) to another LMWH is no longer recommended. The use of unfractionated heparin, danaparoid or hirudin may be warranted in the event of recurrence with fondaparinux, and an immuno-allergological work-up is needed to specify the exact profile of cross-allergies.     

Widespread skin necrosis associated with unfractionated heparin therapy in a patient under chronic coumarin anticoagulation

Coumarins and heparins are commonly used for temporary or long-term anticoagulation. These molecules have potentially devastating side-effects, including widespread skin necrosis. We report the case of an elderly patient under oral anticoagulation with coumarins, who developed widespread necrotic cutaneous lesions upon introduction of intravenous and subcutaneous unfractionated heparin administration for a surgical procedure. Laboratory investigations revealed the presence of circulating antibodies directed against heparin-platelet factor 4. The lesions slowly resolved after withdrawal of heparin, whereas oral coumarin was re-introduced without complications. This case illustrates the rare occurrence of skin necrosis as a result of unfractionated heparin in a patient under chronic coumarin medication. Recognition of this rare complication and appropriate laboratory testing is mandatory for prompt institution of alternative anticoagulant therapies.     

HEPARIN-ASSOCIATED THROMBOCYTOPENIA AND THROMBOSIS (HATT) PRESENTING WITH LIVEDO RETICULARIS

Background. Heparin-associated thrombocytopenia and thrombosis (HATT) is an infrequently encountered syndrome characterized by ischemic necrosis of soft tissue and vital organs following anticoagulation with heparin. The syndrome is thought to be due to heparin-dependent platelet aggregation and thrombosis, which is mediated by pathologic immunoglobulins. Case Report. A 60-year-old man developed truncal livedo reticularis and ischemic necrosis of the left foot associated with thrombocytopenia, disseminated intravascular coagulopathy (Die), and microangiopathic hemolytic anemia during intravenous heparin therapy. Skin biopsy from an area of livedo reticularis revealed fibrin thrombi in dermal blood vessels, which is characteristic of HATT. The diagnosis of HATT prompted discontinuation of heparin and a resulting rapid resolution of the livedo reticularis and hematologic abnormalities. No other potential causes of Die were identified, and, other than stopping heparin, no specific therapy was employed. Conclusions. Periodic monitoring of platelets should be performed on all patients receiving treatment with heparin, as early detection of heparin-induced thrombocytopenia followed by discontinuation of the drug may prevent life threatening thrombotic complications. HATT should be included in the differential diagnosis of patients with livedo reticularis that occurs during heparin therapy.     

Dermatosis ampollosa hemorrágica a distancia; dos nuevos casos por enoxaparina y revisión de la literatura

Enoxaparin is a low-molecular-weight heparin used in the prevention and treatment of pulmonary thromboembolism and other thrombotic disorders. The most common adverse reactions to enoxaparin are ecchymosis, skin necrosis, urticaria, angioedema, and eczema. The first 2 cases of bullous hemorrhagic dermatosis in areas distant from heparin injection sites were described in 2006.We present the cases of 2 men, aged 68 and 78 years, with progressive, advanced-stage lung cancer, who consulted with bullous hemorrhagic lesions without associated symptoms. Both patients reported that the lesions had appeared after initiation of heparin therapy at therapeutic doses.In our review of the literature, we found just 7 cases of heparin-induced bullous hemorrhagic dermatosis. We report a further 2 cases, caused by enoxaparin, in which treatment was continued and in which the lesions resolved in 2 to 3 weeks.     

CUTANEOUS HEPARIN NECROSIS ASSOCIATED WITH GLOMERULONEPHRITIS

Cutaneous heparin necrosis was complicated by glomerulonepbritis, nephrotic syndrome and renal failure. Despite spontaneous resolution of skin lesions, glomerulonephritis progressed and was treated witb cyclophosphamide and prednisone with a good response. Glomerulonephritis complicating anticoagulant induced skin necrosis bas not been described previously, and may be due to vasculitis. Routine monitoring of renal function in this condition may reveal further cases.     

Nicolau syndrome due to hyaluronic acid injections

Six cases of vascular compromise after hyaluronic injection are reported. Clinical symptoms realized a Nicolau syndrome, which is characterized by immediate pain, livedoid pattern and a few days later by the appearance of scabs and skin necrosis. This type of complication is rare, but may be dramatic and injectors must be aware of that. A thorough knowledge of facial anatomy is mandatory to avoid the risky facial areas. The use of a flexible cannula instead of a sharp needle has much less risk of hurting vessels and must be preferred. The support of the patient is discussed and a treatment protocol is proposed.     

Retiform purpura in plaques: a morphological approach to diagnosis

Retiform purpura (RPP) is a livedoid pattern of cutaneous haemorrhage that may result from vasculitis, occlusion or altered coagulation. When this pattern presents as palpable plaques, vascular inflammation is present, and the differential diagnosis includes calciphylaxis, warfarin-induced skin necrosis, antiphospholipid antibody syndrome and heparin-induced skin necrosis. These diseases are clinically aggressive and may result in significant morbidity and mortality. Early recognition is essential to make the necessary medication changes and to begin intervention. Our morphological approach to diagnosis differs from traditional methods and can expedite management. Biopsy results and laboratory findings are then used to verify the diagnosis and determine the specific cause. This approach may allow the development of a treatment plan prior to availability of all ancillary data. Clinical and histological cases are presented for these four syndromes presenting as RPP.     

Warfarin skin necrosis associated with protein S deficiency and a mutation in the methylenetetrahydrofolate reductase gene

The use of warfarin is rarely complicated by skin necrosis. We describe a 50-year-old woman who presented with a left leg deep venous thrombosis and subsequent pulmonary embolism. She was initially anticoagulated with low-molecular weight heparin and subsequently warfarin. Within 4 days abdominal skin necrosis developed. Investigations revealed the presence of protein S deficiency and in addition, a mutation in the methylenetetrahydrofolate reductase gene (MTHFR). We present, to our best knowledge, the first case of warfarin skin necrosis associated with a methylenetetrahydrofolate reductase mutation.     

Leflunomide-induced skin necrosis

BACKGROUND: Leflunomide is prescribed in inflammatory rheumatisms. Cutaneous side effects have rarely been described. We report the case of a patient presenting skin necrosis attributed to this drug. PATIENTS AND METHODS: A 73-year-old woman had been taking leflunomide for psoriatic arthritis for one year and subsequently, developed three abdominal ulcerations and necrosis of one hallux. No immunological, vascular or neoplastic aetiology was found. Corticotherapy was started, based on a hypothesis of vasculitis, but lesions progressed, leading to amputation of the hallux. Leflunomide was stopped and the ulcerations healed completely within 12 weeks, whereas prolonged local treatment had failed to yield any improvement. DISCUSSION: Skin necrosis due to leflunomide is rare; we found seven cases in the literature. Ulcerations may occur anywhere. Potentially life-threatening glomerulonephritis with mesangial deposits may be associated. Discontinuation of leflunomide followed by wash-out with cholestyramine allows healing. Corticosteroids or cyclophosphamide are sometimes necessary. The ulcerations appear to be result from excessive immunomodulation in the skin or from an inhibiting role of leflunomide on the epidermal growth factor receptor. CONCLUSION: In the absence of any demonstrated aetiology in patients presenting ulcerations or skin necrosis, a contributory role of leflunomide must be considered, even in cases of prolonged use.     

Subcutaneous fat necrosis of the newborn with hypercalcemia

INTRODUCTION: Hypercalcemia associated with subcutaneous fat necrosis of the newborn is a well known but rare event. CASE REPORT: A newborn with a history of cesarean section, fetomaternal infection, neurological and respiratory distress was admitted with anorexia, adynamia, vomiting, polyuria and polydipsia at the age of 37 days. Physical examination showed red and violaceous infiltrated skin lesions. Skin biopsy revealed focal areas of fat necrosis with crystal-like structures. Calcium and 1,25 (OH(2) ) vitamin D serum levels were increased. Diagnostic of subcutaneous fat necrosis of the newborn with symptomatic hypercalcemia was made. Evolution was favorable after treatment including furosemide, prednisone and a diet low in calcium and vitamin D. DISCUSSION: Hypercalcemia must be detected in infants with subcutaneous fat necrosis. This major complication may have fatal outcome. Treatment of hypercalcemia includes dietary changes associated with classic treatment of hypercalcemia. Routine evaluation of serum calcium level is essential.     

Atypical purpura fulminans with benign monoclonal gammopathy

A 67-year-old woman with a history of thrombophlebitis had been taking warfarin sodium for 1 1/2 years when she developed multiple skin lesions resembling warfarin-induced skin necrosis or purpura fulminans. Despite discontinuing the warfarin and administering prednisone, the lesions increased in size. Disseminated intravascular coagulation (DIC) was found and resolved with heparin sodium therapy, and her skin lesions healed. This patient was believed to have an atypical form of purpura fulminans rather than warfarin-induced skin necrosis because of the duration of warfarin therapy and the dramatic resolution with heparin. A monoclonal (IgG) gammopathy was found, which stabilized as the skin lesions resolved, and fulfilled the criteria for a benign (asymptomatic) monoclonal gammopathy.     

Clopidogrel: mechanisms of action and review of the evidence relating to use during skin surgery procedures

Patients who have skin surgery may be taking medication that increases the likelihood of bleeding, such as clopidogrel, aspirin, warfarin, heparin and nonsteroidal anti‐inflammatory drugs (NSAIDS). All of these may increase the risk of perioperative and postoperative bleeding. This article examines the mechanism of action of clopidogrel, current practice, and evidence for or against continuing its use during skin surgery. The mechanisms of action of aspirin, warfarin, heparin and NSAIDS will also be briefly discussed.