Are You Confident of the Diagnosis?

Diagnostic criteria

The diagnostic criteria for heparin necrosis can be summarized as follows:

  • Discrete areas of painful cutaneous hemorrhagic necrosis, which initially develop at the injection sites but subsequently involves more distant locations.

  • Antecedent history of heparin administration, typically initiated 5 days prior to the onset of the lesions.

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  • Associated immune-mediated thrombocytopenia resulting in a 50% reduction in platelet count. An absolute platelet count of below 300×109/L is acceptable, although typically the platelet count falls to below 150×109/L.

  • A biopsy of the necrotic plaque edge, stained with hematoxylin and eosin, demonstrates intravascular thrombi throughout the dermal vasculature in the absence of any significant inflammatory cell infiltrate. Biopsy from established plaques may also demonstrate thrombus reorganization.

What you should be alert for in the history

Characteristically patients first experience excessive pain at the site of heparin injection, which typically begins 5 days after the start of heparin treatment. Each site then remains painful as the overlying tissue undergoes hemorrhagic necrosis. With continued heparin administration, as well as a few days after its discontinuation, new lesions can continue to evolve progressively, occasionally involving more distant sites. In the case where heparin treatment is continued, the continued generation of thrombi can affect other organs, which may result in a cerebrovascular accident, myocarial infarction or pulmonary embolus.

Characteristic findings on physical examination

Initially lesions appear as tender dusky erythematous plaques, which then evolve into painful black necrotic plaques; often with a erythematous/hyperemic border (Figure 1).

Figure 1.

A typical necrotic plaque due to heparin necrosis affecting the left thigh, showing the erythematous border due to peripheral vasodilatation.

Hemorrhagic necrosis of the skin results from the sudden occlusion of dermal blood vessels, associated with limited localized hemorrhage from those vessels. Diseases that present with hemorrhagic skin necrosis can be conveniently divided into those that are primarly caused by (a) hypercoagulability, such as heparin necrosis; (b) inflammation of blood vessels, such as the vasculitides; or (c) stagnant or absent blood flow, such as hypotensive shock; as outlined in Table I.

Expected results of diagnostic studies

As alluded to earlier, the diagnosis of heparin necrosis can be confirmed by demonstrating (a) characteristic histopathology, and (b) fall in platelet count, but can also include (c) measuring the pathogenic antibody titer.

A skin biopsy for histology must be taken from the edge of the freshest lesion, do not only take a biopsy from the necrotic plaque itself. Histologic sections stained with hematoxylin and eosin from the edge of the lesion reveal diffuse intravascular thrombi throughout the dermal vasculature, in the absence of a significant inflammatory infiltrate. In established necrotic plaques, this may be associated with thrombus reorganization.

Characteristically, there is a drop in platelet count of greater than 50%, but the change in absolute platelet numbers will depend on the original platelet count. For example, postoperative patients typically have a thrombocytosis while many patients who are in intensive care units have a relative thrombocytopenia.

While not essential for the diagnosis, both ELISA and functional serotoinin release assays are available to determine the titer of the most common causative antibody—see below for details.

Who is at Risk for Developing this Disease?

Heparin is standard therapy for the prevention and treatment of arterial and venous thromboembolic disease, in both adults and children. Heparin necrosis is a rare immune antibody-mediated thrombotic complication caused by heparin-induced thrombocytopenia (HIT). Between 1 and 10% of adults and less than 1% of children and neonates develop HIT; of these, between 29% and 88% (depending on their premorbid state) also suffer arterial or venous thrombosis. The risk of HIT-associated thrombosis appears to be greater when heparin is administered after orthopedic surgery, as well as to those with a history of thrombocytopenia, peripheral arterial disease, or venous thrombosis.

What is the Cause of the Disease?

All heparin types, including both unfractionated and low molecular weight heparin, can cause heparin necrosis, irrespective of the dose. (This can even occur with heparin intravenous flushes.)


Approximately 5 days after exposure to heparin, patients who develop HIT and subsequently heparin necrosis do so because of an immune response that results in antibodies that bind the heparin-platelet factor 4 complex. The antibodies are also bound by the Fc gamma receptor IIa on platelets, thus bringing together platelets and the heparin-platelet factor 4 complex leading to their activation, consumption and thrombosis. In addition the antibody bound heparin-platelet 4 complex is also able to directly stimulate endothelial cells to express prothrombotic factors. Thus in summary, heparin induced antibody immunity leads to a hypercoagulable state, characterized by high serum thrombin-antithrombin complex levels.

Systemic Implications and Complications

Rather ironically, HIT and therefore also heparin necrosis are acquired transient prothrombotic disorders caused by an anticoagulant. The continued administration of heparin is associated with both arterial and veous thrombosis, which can lead to catastrophic complications such as acerebrovascular accident, myocial infarction and pulmonary embolus. Amongst these potential thrombotic complications, approximately 10% of HIT sufferers develop cutaneous manifestations including heparin necrosis.

Coumadins (warfarin) are often given together with heparin to those needing long-term anticoagulation. It is therefore also ironic that patients who develop HIT are at 100-fold greater risk of developing Coumadin necrosis, in particular peripheral gangrene. This probably results from the Coumadin-induced transient decrease in protein C serum levels, a natural anticoagulant, which in this case adds to the overall hypercoagulable state. Likewise platelet trasfusions used in an attempt to reverse the effect of HIT also increase the risk of thrombosis, by providing further substrate for the pathogenic antibody.

Treatment Options

Discontinue heparin administration.

Optimal Therapeutic Approach for this Disease

The immediate priority in managing patients with heparin necrosis is to achieve safe anticoagulation. Discontinuation of heparin will stop the stimulus for antibody production but will also mean withdrawal of its anticoagulant effect. In addition to the prothrombotic heparin-induced antibodies, the original reason for anticoagulation will still be present. For this reason it is important to start an alternative anticoagulant, such as direct anti-thrombin treatment: danaparoid (not available in the USA), lepirudin, or argatroban (not available in the UK). At present there is insufficient evidence to support the use of fondaparinux.

As mentioned earlier, there is an increased risk of Coumadin necrosis. Therefore, if the patient is also receiving Coumadin long-term anticoagulation, it must be stopped and the effects reversed by administration of intravenous vitamin K. Moreover, Coumadins increase the activated partial thromboplastin time, a test necessary for the dosing of direct anti-thrombin treatment. Only when the platelet count has returned to normal, meaning that HIT has resolved, can Coumadins be considered safely for long-term anticoagulation.

Patient Management

In the management of heparin necrosis, the dermatologist is key for making the diagnosis; however, management thereafter depends on a multidisciplinary approach. For example, the optimal anticoagulation protocol for the patient will need to be decided upon with help from the local hematologist. The extent of cutaneous involvement, and importantly extracutaneous manifestations, will define which other specialists will be required to help. In managing the skin necrosis the following important points will need to be considered:

  • Does the severity of the disease necessitate hospital admission? If so what is the ideal setting (eg, intensive care unit)?

  • Does the severity of pain necessitate analgesia? Often patients are in extreme pain requiring both opioid analgesia as well as inhaled nitrous oxide for dressing changes.

  • Does the location of the necrotic plaques predispose to further pressure damage? As pressure damage can aggravate tissue damage, pressure redistribution cushions and mattress may be necessary.

  • Are the patient’s nutritional requirements being met? Wound healing is a catabolic process, with increased nutritional/caloric requirement. Assessment by a dietician may be important to ensure healthy healing.

  • Are the areas of skin necrosis evolving or well demarcated? It takes time for the areas of necrosis to be established so that there is a clear boundary between necrotic and healthy tissue. While the process of demarcation is occuring, it is important to ensure that patient remains well perfused with adequate nutrition. Hydrating dressings (eg, hydrogels) may be used to promote gentle debridement during this phase. Also these areas pose a risk for infection, which will manifest with an increase in pain, erythema, tenderness and warmth. To reduce the risk of infection antiseptics may be used, but once local wound infection is established antibiotic treatment is often necessary.

  • Is the area of necrosis large enough to warrant surgical intervention? While a small areas of skin necrosis can be left to spontaneously heal, larger areas of skin involvement will benefit from surgical debridement, with either simultaneous or delayed skin grafting.

Unusual Clinical Scenarios to Consider in Patient Management

Systemic manifestations associated with HIT and heparin necrosis can be a manifestation of internal thrombosis. For example, thrombosis of the adrenal veins can result in adrenal hemorrhagic necrosis, presenting with pain, an acute abdomen and adrenal crisis. In addition, an intravenous heparin bolus during HIT can trigger an acute systemic reaction characterized by fever, tachycardia, hypertension, shortness of breath, diarrhea, and neurological sequelae.

What is the Evidence?

Patel, GK. “How to diagnose and treat haemorrhagic skin necrosis”. WOUNDS UK. vol. 3. 2007. pp. 40-54. (Expansive review of skin necrosis including HIT.)

Wakentin, TE, Sheppard, JA, Horsewood, P, Simpson, PT, Moore, JC, Kelton, JG. “Impact of patient population on the risk for HIT”. Blood. vol. 96. 2000. pp. 1703-8. (Attempts to reveiw patient characteristics, heparin types, and the serological assays used in making the diagnosis of HIT.)

Schmugge, M, Risch, L, Huber, AR, Benn, A, Fischer, JE. “Heparin-induced thrombocytopenia-associated thrombosis in pediatric intensive care patients”. Pediatrics. vol. 109. 2002. pp. 1-4. (Reviews HIT in the pediatric population.)

Warkentin, TE. “An overview of the heparin-induced thrombocytopenia syndrome”. Semin Thromb Hemost. vol. 30. 2004. pp. 273-83. (HIT syndrome: in-depth discussion and clinical and treatment review.)

Patel, GK, Knight, AK. “Generalised cutaneous necrosis: a complication of low-molecular-weight heparin”. Int Wound J. vol. 2. 2005. pp. 267-70. (Overall review of heparin-induced skin necrosis.)

Visentin, GP, Ford, SE, Scott, JP, Aster, RH. “Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells”. J Clin Invest. vol. 93. 1994. pp. 81-8. (The authors describe the findings of specific antibody formation in cases of HIT.)

Warkentin, TE. “Think of HIT”. Am Soc Hematol Educ Program. 2006. pp. 408-14. (Nice review of when to consider the diagnosis, and to remind the clinican to be vigilant for it.)

Warkentin, TE, Elevathil, LJ, Hayward, CPM, Johnston, MA, Russett, JI, Kelton, JG. “The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia”. Ann Intern Med. vol. 127. 1997. pp. 804-12. (Discusses mechanisticls of the pathophysiology of gangrene caused by heparin induced thrombocytopenia.)

Keeling, D, Davidson, S, Watson, H. “The management of heparin-induced-thrombocytopenia”. Br J Haematol. vol. 133. 2006. pp. 259-69. (Excellent review of the disease and its management.)