Description of the condition
Data from the World Health Organization (WHO) estimated that in 2011 approximately 366 million people worldwide had diabetes mellitus (DM) (Wild 2004); over 80% of DM is thought to occur in low- and middle-income countries (Bakker 2012a). The International Working Group on the Diabetic Foot (IWGDF) defines a diabetic foot ulcer as a 'full-thickness' lesion of the skin (Bakker 2012a). It occurs in 16% of people with DM and precedes 85% of foot-related amputations (Brem 2007). The prevalence of diabetic foot ulcers varies from country to country. In the USA, the lifetime incidence of developing a diabetic foot ulcer may be as high as 25% for the 24 million people with DM, with 1% of this population requiring amputation (Sherman 2010). Every year In Germany 22,000 people with DM lose a leg as a result of diabetic foot ulcers (Simson 2008). South Asians with DM are about 33% more likely to develop a foot ulcer than Europeans (Abbott 2005). The prevalence of diabetic foot ulcers is about 5.6% of those with DM in the Veterans Affairs Hospital of America Seattle, 10.2% in Britain, 10% in India and 14% in China (Li 2010).
Diabetic foot ulcers are caused by multiple pathogenic (disease) mechanisms (Warren 2009). The most frequent etiologies (causes) are peripheral sensory neuropathy (damage to nerves in feet/legs), trauma, deformity, high plantar pressures (pressure on the foot when walking), and peripheral arterial disease (Boyko 1999; Frykberg 2009; Reiber 1999). The etiology of diabetic foot ulcers can be grouped into three major classifications: neuropathic (due to damage of the nerves); ischaemic (due to a poor blood supply); or neuroischaemic (due to damage to the nerves and a poor blood supply). The loss of sensation caused by peripheral neuropathy means that injuries to the feet may not be noticed when they happen, and these, potentially, can develop into more serious wounds. If the blood supply is partially or completely blocked, tissue will begin to die, which can result in the development of painful ulcerations on the feet. For healing to occur it is of crucial importance to have intact microcirculation in the skin around the ulcer, and adequate arterial blood supply to the ulcer area. Hyperglycaemia (high blood sugar levels) can decrease fibrinolytic activity, which increases blood viscosity and induces a high coagulation state in people with DM (Creager 2003). The high coagulation state can damage vessel walls and lead to vascular dysfunction, coagulation-anticoagulation disorders and haemorrheological (blood) disturbances (Mekkes 2003). This high coagulation state contributes to the slow healing of diabetic foot ulcers..
There are five criteria that are commonly considered to be the most relevant when grading diabetic foot ulcers, namely: perfusion; extent/size; depth/tissue loss; infection; and sensation. Grading systems score an ulcer in terms of either presence or absence, or severity, for each of these criteria. For instance, the Wagner grading system has five grades based on the severity of infection: Grade 1 - superficial diabetic ulcer; Grade 2 - ulcer extension; Grade 3 - deep ulcer with abscess or osteomyelitis; Grade 4 - gangrene to portion of forefoot; and Grade 5 - extensive gangrene of foot (Wagner 1987).
Diabetic foot ulcers are a significant personal health issue for those who have them, and are associated with a considerable economic burden that impacts significantly on healthcare systems. In the USA, the costs of diabetic foot ulcers were estimated as US $40 billion each year. When compared with a person who has DM but no foot ulcer, the cost of diabetic patients with a foot ulcer is 5.4 times higher in the year after the first ulcer episode, and 2.8 times higher in the second year. Costs for the treatment of the highest-grade ulcers are eight times higher than for low-grade ulcers (Cavanagh 2012; Driver 2010).
Description of the intervention
There are multiple approaches to treating foot ulcers in people with DM that include: glycaemic (blood sugar level) control; diet control; standard care for ulcers; correction of arterial insufficiency; resection of the chronic wound (ulcer); and the use of wound dressings (Game 2012). In 2012, guidelines from the IWGDF recommended that the main principles of ulcer treatment should be: 1) relief of pressure and protection of the ulcer; 2) restoration of skin perfusion; 3) treatment of infection; 4) metabolic control and treatment of comorbidity; and 5) local wound care (Bakker 2012b).
Heparin and heparin-related (i.e. 'related') substances are glycosaminoglycans (GAGs); these are polysaccharides whose classification is based on core disaccharide (two sugar) groups that repeat. Heparin is a GAG of mixed composition, i.e. molecules of different lengths. It has potent anticoagulant properties that are used to treat and prevent clotting disorders where there is excessive or undesirable clotting, including, thrombophlebitis (clot in vein), acute myocardial infarction (heart attack), stroke, and pulmonary embolism (clot in lung). Heparins can be separated into two groups: unfractionated heparin (UFH) (heparin in a range of molecular sizes), and low-molecular-weight heparin (LMWH) (smaller heparin molecules). Both these are potent antithrombotic (anti-clotting) agents that also enhance fibrinolytic activity and have anti-inflammatory effects. UFH is a naturally-occurring polysaccharide that works as an anticoagulant by inhibiting the activity of several blood coagulation factors. Laboratory work has shown that heparin-induced precipitation of low-density lipoprotein in the blood causes a reduction in the levels of fibrinogen (a clotting agent). This effect, if transferable to people, could lead to the confining of necrotic tissue and a reduction in the amputation rate in people with severe diabetic foot syndrome (Rietzsch 2008). Studies have claimed that heparin can improve haemorrheological parameters, increase arterial blood supply and enhance healing in patients with diabetic foot ulcers (Bonnie 2011; Li 2002). LMWHs consist of short chains of polysaccharide, obtained from various methods of fractionation (separation) or enzymatic depolymerization (cutting) of UFH (Linhardt 1999). LMWH has advantages for the treatment of diabetic foot ulcers compared to UFH. Firstly, LMWH has more favourable bioavailability and pharmacokinetics, so it can be administered subcutaneously without monitoring. Secondly, LMWH may result in fewer bleeding complications due to a less pronounced effect on platelet function and vascular permeability (Hirsh 2001), which means that it can be used long-term as an out-of-hospital treatment because of its relative safety. Subcutaneous injection of dalteparin, one type of LMWH, can improve the capillary circulation in the ulcer margin, which positively influences the healing process of chronic foot ulcers in diabetic patients (Jorneskog 1993). Rullan indicated that diabetic foot ulcers treated with bemiparin, another LMWH preparation, administered once daily by subcutaneous injection were observed to have better ulcer improvement rates, complete healing rates and few adverse reactions (Rullan 2008).
LMWHs are a class of anticoagulants that includes enoxaparin, nadroparin, dalteparin, tinzaparin, bemiparin, and reviparin. Related substances include: chondroitin, heparitin sulphate, hyaluronic acid and keratan sulphate. Chondroitin is a GAG composed of a chain of alternating sugars, usually attached to proteins, as part of a proteoglycan. Heparitin sulphate is a polysaccharide containing the same repeating disaccharide groups as heparin. Hyaluronic acid is a GAG distributed widely throughout connective, epithelial, and neural tissues. Keratan sulphate is, like other GAGs, a linear polymer that consists of a repeating disaccharide unit; it is found especially in the cornea, cartilage, and bone.
How the intervention might work
Heparin and related substances are GAGs that exist naturally inside the cell and in the extracellular matrix (fluid outside cells). They act by binding selectively to varieties of proteins and pathogens (disease-causing agents) and are crucially relevant to many disease processes (Gandhi 2010; Shafritz 1994).They have beneficial effects on local tissue microcirculation and oxygenation through the inhibition of thrombin generation and increases in plasma fibrin gel porosity, which may promote vascular perfusion in the ischaemic foot significantly and lead to improvements in its blood supply. They can promote healing of chronic ulcers by stimulating production of basic fibroblast growth factor and transforming growth factor-beta 1 (Carroll 2003). Laboratory work has also shown that they have positive effects in vitro, including promotion of the synthesis of heparin sulphate in endothelial cell cultures (Cavanagh 2012), and the proliferation of fibroblasts (cells involved in wound healing) obtained from diabetic ulcers (Warren 2009). Heparin can promote neo vascularisation (growth of new blood vessels) in ischaemic limbs by improving the structure and number of capillaries (Bakker 2012b; Game 2012). All these activities mean that heparin and related substances might act as a scaffold to enhance the activity of growth factors and reduce the inflammatory response in the ulcer bed.
Why it is important to do this review
Some published studies have demonstrated positive effects for heparin and related substances on the healing of diabetic foot ulcers (Kalani 2003; Rullan 2008), but most of these have methodological limitations. As far as we know, there are, as yet, no systematic reviews addressing this topic. Consequently, a systematic review of the available evidence for the efficacy and safety of heparin and related substances for diabetic foot ulcers is required.