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Oremus M, Hanson M, Whitlock R, et al. The Uses of Heparin To Treat Burn Injury. Rockville (MD): Agency for Healthcare Research and Quality (US); 2006 Dec. (Evidence Reports/Technology Assessments, No. 148.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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The Uses of Heparin To Treat Burn Injury.

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Heparin belongs to a family of polyanionic polysaccharides called glycosaminoglycans (GAGs). The structure of GAGs is described in terms of their prevalent repeating disaccharide sequences, which consist of alternating uronic acid and amino sugar residues. Heparin is a highly sulfated polysaccharide composed of hexuronic acid and D-glucosamine residues joined by glycosidic linkages.1

Heparin is a polydisperse compound with a molecular weight ranging from 3,000 to 30,000 Da (Daltons) (mean weight, approximately 15,000 Da). Commercial heparin, or unfractionated heparin (UFH), is isolated from mammalian tissues rich in mast cells. Heparin acts as an anticoagulant by activating antithrombin and accelerating the rate at which antithrombin inactivates clotting enzymes, particularly thrombin (factor IIa) and factor Xa. UFH also enhances the inhibition of factor IXa, factor XIa, and factor VIIa bound to tissue factor by antithrombin. Heparin binds to antithrombin through a high affinity pentasaccharide, which is present on about one-third of heparin molecules. Binding of heparin to antithrombin via its unique pentasaccharide sequence causes a conformational change in the reactive center loop of antithrombin that accelerates its interaction with factor Xa, but not with thrombin. For inhibition of thrombin, heparin must bind to both the coagulation enzyme and antithrombin. This bridging effect requires a heparin chain that contains at least 18 saccharides. By inactivating thrombin, heparin not only prevents fibrin formation, but also inhibits thrombin-induced activation of platelets and factors V and VIII.2

Besides binding to antithrombin, heparin also binds to a wide range of other proteins via electrostatic interactions. These proteins include heparin cofactor II, receptors, and growth factors. The relative strength of binding depends on the sulfation pattern, charge density, and molecular weight.2

Low Molecular Weight Heparins

During the last decade, low molecular weight heparins (LMWHs) have gradually replaced UFH for some clinical indications. LMWH is prepared from UFH by controlled enzymatic or chemical depolymerization. Like heparin, LMWHs are polydisperse and comprise heparin chains from 1,000 to 10,000 Da. The mean molecular weight of LMWHs is between 3,600 and 6,500 Da. About 15 to 20 percent of LMWH chains contain the antithrombin-binding pentasaccharide sequence. At least half of the pentsaccharide-containing chains of LMWH are too short to bridge thrombin to antithrombin. For this reason, LMWHs have reduced ability to inactivate thrombin. In contrast, the smaller molecular weight chains retain their ability to inactivate factor Xa because bridging between antithrombin and factor Xa is less critical. Compared to UFH, LMWHs exhibit a better subcutaneous bioavailability, a more predictable anticoagulant response, and a longer half-life.3 More recently, synthetic analogs of the antithrombin-binding pentasaccharide sequence have been developed.4

Non-Anticoagulant Effects of Heparin

Heparin possesses both a flexible structure and a high anionic charge that permits electrostatic interactions with a variety of different molecules. While heparin has been used largely for its anticoagulant effects, there is evidence that heparin and related molecules also possess anti-inflammatory and antiangiogenic properties, as well as a capacity for wound healing. These effects are discussed separately below.

Anti-Inflammatory Effects

Although the mechanisms responsible for the anticoagulant effects of heparin are well understood, the mechanisms underlying heparin's anti-inflammatory activity are not. The evidence that heparin possess anti-inflammatory properties comes mainly from cell culture and animal studies. The anti-inflammatory and immunomodulating effects are far-reaching and include influencing monocyte, T-cell and neutrophil activity, nitric oxide production, chemokine and cytokine activity, complement activity, platelet activation and aggregation, and smooth muscle cell proliferation.5

Antiangiogenic and Antimetastatic Effects

There is increasing interest in a potential role for heparin and related molecules in the management of cancer patients.6 LMWHs have generated particular interest because they have been validated in both the treatment and prevention of thromboembolic disease in patients with malignancy. More interestingly, the benefits of LMWH therapy appear to be independent of any anticoagulant properties, which suggests that direct effects on tumor cell biology can help to explain the mechanism. Possible mechanisms include the inhibition of selectin-mediated cell-cell interactions, heparanase inhibition, binding of proangiogenic growth factors (e.g., basic fibroblast growth factor [bFGF] and vascular endothelial growth factor [VEGF]), and stimulation of tissue factor pathway inhibitor (TFPI) release.7

Wound Healing Effects

A persistent inflammation with the accumulation of large numbers of neutrophils is characteristic of chronic wounds. Secretory products released from these cells, such as elastase, cathepsin G, and proteinases, are detrimental to wound healing because they degrade the extracellular matrix and growth factors and further recruit neutrophils to the wound area. Heparin and related molecules are thought to inhibit the action of these secretory products via electrostatic interactions.8, 9

Clinical Uses of Heparin

Since its discovery in 1917, heparin preparations have been used as an effective anticoagulant for thromboembolic prophylaxis and treatment.1013 With over half a century of use, other roles for heparin have been elicited, including angiogenesis regulation, lipoprotein lipase modulation, maintenance of endothelial competence, and inhibition of vascular smooth muscle proliferation after injury.14 This section will focus on clinically proven and accepted applications of heparin.

Heparin is the most widely used parenteral antithrombotic in clinical medicine due to its ease of administration and titration, availability, cost, known side-effect profile, and demonstrated clinical efficacy. Other parenteral antithrombotic agents available include heparinoids such as fondaparinux or direct thrombin inhibitors such as hirudin and bivalirudin. These drugs are more expensive, not as easily titrated and reversed, and have been studied in fewer clinical applications relative to heparin. Numerous guidelines define the role of heparin in thrombosis prevention and treatment; the American College of Chest Physicians (ACCP) guidelines are perhaps the most frequently cited. See Baglin et al. for a review of these guidelines.15 Clinical indications for heparin have been divided into (1) thrombosis prevention and (2) thrombosis treatment (See Tables 1 to 3 below).

Table 1. Accepted indications for heparin prophylaxis.

Table 1

Accepted indications for heparin prophylaxis.

Table 3. Accepted indications for heparin treatment - arterial and other.

Table 3

Accepted indications for heparin treatment - arterial and other.

Thrombosis Prevention

Subcutaneous heparin has been demonstrated to reduce the incidence of venous thromboembolism in several clinical scenarios. Table 1 summarizes both the clinical indications and level of evidence for using heparin in this treatment area. Grades of evidence from Tables 1 to 3 are explained in Table 4.

Table 4. Grades of evidence.

Table 4

Grades of evidence.

Thrombosis Treatment

Heparin, in the absence of heparin induced thrombocytopenia (drop in platelet number), is the initial anticoagulant of choice for treating thrombotic processes (blood clots) involving veins and arteries. Tables 2 and 3 contain generic summaries of clinical scenarios where therapeutic heparin is indicated for treating thrombotic processes.

Table 2. Accepted indications for heparin treatment - venous.

Table 2

Accepted indications for heparin treatment - venous.

As shown above, in the realm of thromboembolic pathology, heparin plays a major role in clinical medicine.

Burn Injury

Approximately 1.25 million people are treated annually for burn injuries in the United States. Four percent of these people require hospitalization and specialized burn care. High-risk populations for burn injuries include children, elderly, physically or mentally disabled, and people in military service.40, 41

Definition and Description of Burn Injury

Burn injuries are either partial thickness or full thickness in nature. Partial thickness burns involve the epithelium and various depths of the underlying dermis. These burns are diagnosed both clinically and temporally. Partial thickness burns can be divided into superficial or deep partial thickness burns.

Superficial partial thickness burns appear as an erythema (first degree) or blistering (second degree) on the skin. Very superficial burns correlate with injury to the epithelial layer of skin and usually heal without medical intervention or scarring (except for possible hyperpigmentation, which is usually temporary in nature [e.g., sunburn]). Superficial partial thickness burns heal within 7 to 14 days.

A superficial partial thickness burn may also involve the superficial aspect of the dermis (second degree), which can result in blistering and scarring of the skin. The presence of varying shades of foci of pallor indicates deep partial thickness burns that heal within six weeks. However, healing may be incomplete. These burns scar the skin and frequently require surgical debridement and grafting.

Full thickness burns result in injury and loss of the entire epithelium and dermis (third degree). A full thickness burn may also involve injury to underlying structures such as muscles, nerves, tendons, or bones (fourth degree). If left on their own, without surgical intervention, these burns would take well in excess of six weeks, or even months, to heal. These burns may cause significant scarring and, if present around joints, may severely limit the range of motion.42

Partial Thickness

First degree → superficial (erythema)

Second degree → deep (blister, pallor)

Full Thickness

Third degree → white, tan, beige, red, etc. skin color

Fourth degree → involves tendon, bone, etc.

Burn injuries may also be classified according to the type of noxious agent causing the burn (e.g., flame, scald, flash, contact, smoke inhalation, electrical). Scald injuries, the most common burn injury in civilian populations, are secondary to contact with hot liquids. Hot water is the most common cause of scald injury, but other agents can include coffee, tea, soup, sauces, hot grease, or oil. Burns secondary to contact with tar and asphalt are also considered scald injuries. Intentional scalding of children is a common method of child abuse.

Flame burns are secondary to contact with a source of open flame. House fires, careless smoking, automobile accidents, inappropriate use of flammable materials, and ignition of clothing are common factors associated with flame burn injury. Flame burns are associated with a serious and potentially fatal condition known as smoke inhalation injury. Inhalation injury is due to the exposure of the respiratory tract to steam and toxic inhalants from the smoke of a fire.43

Flash burns are secondary to exposure to explosions of combustible or flammable materials. Contact burns are secondary to skin contact with hot items such as metal, glass, chemicals, plastic, or coals. Electrical burns are thermal injuries that occur when electrical energy is converted into heat upon contact with the skin.44 Electrical burns can severely affect deeper structures such as nerves or bones even when there is minimal damage to the overlying skin.

Burn Care

In the past three decades, North American burn care has undergone significant transformation, and this has led to markedly improved survivability.4547 The North American health care system has developed a sophisticated approach to hospital burn care that is predicated on a network of specialized burn treatment centers. These centers are well equipped and professionally staffed to treat local injuries and to handle the transfer and treatment of serious burn injuries from more distant locales. This transformation of burn care reflects advancements in multiple areas of medicine, including critical care, wound infection control and antimicrobial therapy, surgical therapy (e.g., early excision and grafting), specialized burn care research, and coordinated methods of burn patient transfer (e.g., air ambulance and accompanying medical support services).45 Early excisional therapy of deep partial thickness or full thickness burns is a common component of the North American standard of care for burn injury.46, 47 Burns that heal within three weeks commonly do well and are less likely to produce hypertrophic scarring or functional impairment. Burns that require more than three weeks to heal are commonly associated with hypertrophic scarring or functional impairment. For patients with small to moderate burn injuries where the healing time will exceed three weeks, early excision and grafting is the recommended course of treatment. The benefits of early excision and grafting include decreased hospitalization, early return to work or school, enhanced functional status, and improved physical appearance. However, properly estimating the time to healing for a burn remains an important clinical challenge.44 Risk factors associated with mortality in burn injury include total body surface area (TBSA) greater than 40 percent, age over 60 years, and inhalation injury.48 Temporary or permanent disabilities are common in patients with significant burn injuries who are admitted to specialized burn care facilities.49 Reconstructive surgery and long-term rehabilitation are routine components of extended care for disabled burn patients.

Psychosocial Aspects of Burn Injury

The morbidity associated with burn injury is not limited to physical conditions such as pain or scarring. Psychiatric and psychosocial morbidities form important and often overlooked aspects of burn injury. Psychiatric and psychosocial morbidities are classified into pre- and post-injury conditions.50, 51 Pre-injury psychiatric conditions in adults may include depression, suicidality, substance abuse, and personality disorders. In children, pre-injury conditions may include behavioral disorders such as conduct disorder or attention deficit hyperactivity disorder.50, 51

In the post-injury phase, hospitalization and acute burn care can lead to psychiatric and psychosocial stresses for patients.50, 51 Common psychiatric conditions include delirium, acute stress disorder (ASD), post-traumatic stress disorder (PTSD), and depression. Psychological suffering (i.e., PTSD) may also be manifest in the parents of children or adolescents with burn injury.52

The first year post-burn injury may be particularly psychologically stressful for patients,51, 53 but most adult50, 51 and pediatric54 burn patients do not suffer long-term, burn-related, psychiatric sequelae.

For a minority of burn injured patients, altered patterns of socialization may develop, especially for men with visible disfigurement. In women, decreased levels of sexual satisfaction are a frequent long-term result of burn injury.51

Heparin and Burns

The non-anticoagulant effects of heparin and related molecules form the rationale for the use of heparin in the treatment of burns. This report will address two main questions related to heparin and burns:


What is the evidence for the benefits and harms of heparin use in thermal injury care?


Does the method of application make a difference?


Do the outcomes vary by the type or degree of burn?


How do the outcomes of burn treatment with heparin compare to current treatment without heparin?


What are the contraindications of heparin use in burns?

Addressing these questions will serve to identify both the strength of the evidence for using heparin to treat burns and gaps in existing research. As well, answering these questions will facilitate the establishment of future research priorities.


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