Critical Limb Ischemia: From Reduced Blood Flow to Tissue Damage

When blood flow falls, tissue health begins to suffer. 

Adequate function of the cells depends on the steady oxygen and nutrients supply and metabolic waste removal. The narrowing or blockage of arteries hampers the supply of blood, oxygen, or nutrients. At the beginning, the effects are limited to discomfort or reduced walking ability. With progression of the condition, the problem moves beyond vascular insufficiency and tissue injury. 

Critical limb ischemia (CLI) is characterised by severe blockage of blood flow in the lower limb of the body. The most critical form of CLI is peripheral artery disease (PAD). The occurrence of CLI leads to persistent pain, non-healing wounds, or ulcers. In advanced cases, the wound worsens and develops into tissue necrosis or gangrene. The underlying cause varies, including atherosclerosis, diabetes, smoking, or the presence of cardiovascular risk factors. The current management approach of CLI involves identification of the blocked artery causes and revascularisation.

However, restoration of the damaged tissue remains a clinical gap. The emerging regenerative approach in the form of stem cell therapy explores the potential of targeting problems at the cellular and molecular level. They can potentially target angiogenic signalling, boost tissue repair, and create a calmer microenvironment. The current article explores the detailed underlying causes of Critical Limb Ischemia and unveils the potential of stem cells to restore circulation, support tissue repair, and improve quality life of the patient.

Ask The Expert

The Circulation–Tissue Connection: What Happens Inside an Ischemic Limb?

Critical Limb Ischemia Alters/Affects Multiple Mechanisms. The Lower Limbs are Severely Affected, Resulting in Intense Persistent Pain. The Key Alterations Include:

• Altered Oxygen Supply: Gradual arterial narrowing leads to blockage of arteries. This limits oxygen and nutrient delivery, which hampers normal cellular function
• Poor Microcirculation: The reduction in blood flow in smaller vessels limits the oxygen supply, even when oxygen flow in the larger vessels is restored
• Cellular Energy Stress: The insufficient oxygen supply leads to a shift away from aerobic metabolism; it increases metabolic stress and compromises normal tissue function
• Endothelial Changes:  Disruption of the endothelial function promotes inflammatory signalling. It creates an unfavourable environment in the unhealthy tissues
• Progressive Structural Injuries: Inadequate perfusion results in cellular damage. The tissue injury progresses, leading to progressive ischemia

Critical Limb Ischemia (CLI) Causes: What Drives the Loss of Blood Supply?

Critical Limb Ischemia Involves Multiple Factors:

• Atherosclerosis: The severe buildup of plaque in peripheral arteries leads to atherosclerosis. The narrowing of the arteries compromises blood flow in the lower leg or foot. The condition leads to leg cramps and achiness due to restricted blood flow
• Hyperglycemia or Vascular Complication: Presence of co-morbid factors like diabetes worsens the condition. Prolonged diabetes damages the blood vessels and delays wound healing
• Thrombosis/ Artery Occlusion: Blood clot or complete blockage of the blood flow due to artery narrowing involves circulatory problems

*NOTE: The key risk factors include ageing (>75), lifestyle problems (smoking), chronic kidney problem, CAD, depression, etc. 

Recognising Critical Limb Ischemia (CLI) Symptoms: Recognising Before Tissue Loss 

Critical Limb Ischemia Symptoms Include:

• Persistent limb or foot pain, resting pain
• Skin sores, non-healing wounds that don’t heal fast
• Discoloured skin (purple, greenish or black)
• Reduced sensation due to tissue damage
• Severe tissue injury leads to nephropathy or gangrene

Mapping the Severity ofCritical Limb Ischemia (CLI): From Blood-Flow Assessment to Tissue Status

Clinicians Diagnose the Underlying Factors and Determine the Critical Limb Ischemia Severity. This Includes: 

• Ankle-Brachial Index (ABI): Comparison of blood pressure of the arms vs the ankles
• Toe-Brachial Index: Comparison of blood pressure of arms vs. toes
• Pulse Volume Recording: Measures volume changes in the blood flow in the leg
• Detailed Health Assessment: Overall health assessment including identification of co-morbid condition status. This includes diabetes. Cardiovascular disease, chronic kidney condition, existing wound, or possible nephropathy.

*NOTE: Critical Limb Ischemia ICD 10 enlists parameters that enable identification of the underlying complications. 

CLI Treatment: Restoring Perfusion and Protecting the Limb

Critical Limb Ischemia Treatment Depends on the Condition Severity, Including:

Medications

• Introduction of antiplatelet drugs and anticoagulants to combat blood clots
• High-dose statins to combat bad cholesterol, limit buildup of atherosclerosis
• Antihypertensive medication lowers hypertension

Surgical Intervention

• Leg revascularization, surgical intervention that enables adequate blood flow in the leg
• Venous arterialization, involves restabilising connection of the arteries with veins
• Wound care and infection control by removal of debridement. This supports healing of nearby tissue. Introduction of antibiotics
• Limb amputation: in the most severe scenarios, the surgeon removes a portion of the affected toe or limb. The patients might be introduced to prosthetics and physical therapy

*NOTE: The conventional critical limb ischemia treatment targets the symptomatic cause. Researchers widely explore regenerative approaches to target the root cause of the problem. 

Where Does Regenerative Medicine Fit Into CLI?

• Intends to restore blood flow supported by the formation of new blood vessels
• Aims to create a supportive local tissue environment
• The area of regenerative medicine is evolving; it is introduced to support other conventional treatments
• Vascular regeneration is still evolving and is at an early stage of clinical application
• Future research focuses on launching large-scale clinical trials to establish the long-term treatment efficacy and safety

Stem Cell Therapy for CLI: Exploring a Regenerative Approach

Stem Cell Therapy for CLI Introduces Changes at the Cellular and Molecular Level. The Key Mechanism Includes:

• Angiogenesis: Stem cells release various growth factors (VEGFs, FGFs, IL8) that promote the formation of new blood vessels. This enables an adequate supply of blood, oxygen, and nutrients at the injury site. They potentially combat microcirculation
• Anti-Inflammation: Stem cells release anti-inflammatory molecules; they combat pro-inflammatory cytokine signals. They efficiently combat low-grade chronic inflammation
• Immunomodulation: Stem cells create a calmer microenvironment and minimize the risk of immune rejection. Clinicians who combine conventional treatment with stem cell therapy show better outcomes
• Tissue Regeneration: Stem cell therapy releases various growth factors. They modulate signalling networks and boost communication between endothelial cells. This improves distal tissue perfusion, promotes healing, and increases oxygen pressure 
• Repair Mechanism: Stem cells modulate repair signalling, it boost body’s normal repair mechanism [1]

*NOTE: Currently, stem cell introduction among CLI patients is still evolving. Preclinical and clinical studies reflected safety and tolerance, but the results varied among individuals. Various factors like stem cell quality, source, isolation procedure, administration, and individual factors impact the outcome. Advancells, India, is a leading manufacturer and supplier of clinical-grade stem cells for various chronic health conditions like critical limb ischemia. The products are supplied with a Certificate of Authentication (CoA)

Key Takeaway

• CLI is characterised by reduced blood flow at the lower limb
• Oxygen deprivation and tissue injury lead to intense resting pain
• Conventional Critical Limb Ischemia Treatment depends on the diseased stage and severity
• Emerging regenerative strategies can potentially support cellular regeneration, reduce inflammation, and facilitate adequate blood supply to the injury site

References

1. Lozano Navarro LV, Chen X, Giratá Viviescas LT, Ardila-Roa AK, Luna-Gonzalez ML, Sossa CL, Arango-Rodríguez ML. Mesenchymal stem cells for critical limb ischemia: their function, mechanism, and therapeutic potential. Stem cell research & therapy. 2022 Jul 26;13(1):345. 

FAQ’s

Q- What is CLI?

Critical Limb Ischemia (CLI) is the most severe form of peripheral arterial disease in which blood flow to the limb becomes significantly reduced. Persistent lack of oxygen can cause pain, non-healing wounds, tissue damage, and, in advanced cases, gangrene.

Q- What are the common symptoms of Critical Limb Ischemia?

Common signs include persistent foot or leg pain, particularly at rest, slow-healing wounds or ulcers, changes in skin colour or temperature, numbness and weakness. A wound that does not heal normally should be evaluated promptly.

Q- What causes Critical Limb Ischemia?

CLI is associated with advanced peripheral artery disease. The arteries become narrowed or blocked. Hypertension, hyperglycemia, smoking, high cholesterol, high blood pressure, and other cardiovascular risk factors can increase the likelihood of developing severe arterial disease.

Q- How is CLI treated?

CLI treatment depends on the extent and location of reduced blood flow. Various options include medicines, risk-factor management, wound care, surgical intervention (angioplasty, stenting, or bypass surgery) or combination of conventional treatment with regenerative approach. This enables restoration of blood flow and improves patient’s quality of life.

Q- Can stem cell therapy help in Critical Limb Ischemia?

Stem cell-based approaches are investigated as a regenerative strategy. The potentially enable blood-vessel formation and healthier tissue microenvironment around ischemic areas. However, this remains an evolving area of research. They are not established vascular treatment.