What is Critical Limb Ischemia?

Critical limb ischemia (CLI) is the most severe form of peripheral arterial disease (PAD) caused by chronic inflammatory processes associated with atherosclerosis that result in markedly reduced blood flow to the legs, feet and hands. There are an estimated 10-12 million people with PAD in the United States1, and over 1 million people with CLI.2 Aastrom Biosciences is currently conducting clinical research and clinical trials to treat CLI and PAD. The figure below shows the PAD continuum from asymptomatic disease to CLI with tissue loss.

Peripheral Arterial Disease Continuum Chart

Ischemia is a reduction in blood supply. The reduced blood flow in CLI is caused by arterial plaque (deposits of fatty material), which reduces the blood flow to the peripheral (outer) part of the body (i.e. legs, feet and hands).

Infographic illustrating how 1.Tissue necrosis can occur distal to site of arterial obstruction 2. Arterial plaque reduces blood flow to peripheral tissues

The condition occurs in slightly more men than women. Diabetes, abnormal cholesterol levels, chest pain, obesity and increased age are all associated with an increased incidence of CLI.3

Symptoms of CLI

Critical limb ischemia symptoms may include:

  • Pain or numbness in the feet or toes
  • Open sores, skin infections or ulcers that will not heal
  • Dry gangrene (dry, black skin) of the legs or feet.


The leg pain caused by CLI can occur even while a person is at rest (“rest pain”), and can be temporarily relieved by hanging the leg over the bed. In fact, rest pain from leg ischemia most typically occurs at night, but in severe cases can be continuous.

CLI Diagnosis and Treatment

The diagnosis of CLI includes a physical examination and non-invasive vascular evaluations. The physician will evaluate skin condition of the limbs (dry skin, thickened nails, loss of hair, loss of fat under the skin, muscle wasting, gangrene), and look for decreased or absent pulses, changes in skin color when the limb is lifted or allowed to dangle, and non-healing wound or ulcer. Non-invasive vascular tests include blood pressure in the limbs.4

Treatment goals for CLI include reducing the number of cardiovascular risk factors (such as quitting smoking and reduction of cholesterol), relieving pain, healing ulcers, preventing major amputation, improving quality of life and increasing survival. There are no drugs currently approved by the Food and Drug Administration for the treatment of CLI. The predominant treatment options for those patients who are eligible are surgical procedures to restore blood flow, or revascularization.

Patients with CLI and “No Option” or “Poor Options” for Revascularization

Many patients with CLI have multiple conditions which may prevent them from having surgery.5 Up to 40% of CLI patients are not candidates for surgery. Major amputation is necessary when there is overwhelming infection that threatens the patient’s life, when rest pain cannot be controlled, or when there is extensive skin and tissue loss.

Clinical trials explore new treatments through stem cell therapy


Experimental treatments for CLI include the use of growth factors, protein therapies, and cell-based therapies. New or ongoing clinical trials for these experimental therapies can be found on ClinicalTrials.gov. ClinicalTrials.gov is a registry of federally and privately supported clinical trials conducted in the United States and around the world. You may also visit our CLI Clinical Trials page to learn more about Aastrom’s trials for critical limb ischemia.

CLI Resources

The useful links below (accessed September 30, 2011) may provide helpful resources for learning more about PAD and CLI.

1E Selvin, T Erlinger. Prevalence of and risk factors for peripheral arterial disease in the United States. Circulation. 2004;110:738-743.

2JM Peacock, HH Keo, X Yu, N Oldenburg, S Duval, TD Henry, et al. Abstract 5788: The incidence and health economic burden of critical limb ischemia and ischemic amputation in Minnesota: 2005-2007. Circulation 2009;120:S1148.

3E. Minar. Critical limb ischaemia. Hamostaseologie 2009 29:102-109.

4D. Slovut and T. Sullivan. Critical limb ischemia: medical and surgical management. Vasc Med 2008 13:281.

5Powell RJ, Simons M, Mendelsohn FO, Daniel G, Henry TD, Koga M, et al. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation. 2008 Jul 1;118(1):58-65.