Chronic Limb-Threatening Ischemia (CLTI)

Chronic limb-threatening ischemia is the clinical manifestation of sustained, critical limb hypoperfusion. It represents a failure of compensatory vascular mechanisms and progression beyond exertional ischemia.

CLTI is typically defined by one or more of the following:

Ischemic rest pain lasting more than two weeks
Non-healing ischemic ulcers
Tissue loss or gangrene
Objective hemodynamic evidence of arterial insufficiency

Ischemic Rest Pain

Ischemic rest pain reflects inadequate perfusion at baseline metabolic demand. It most commonly involves the forefoot or toes and is frequently described as:

Burning, aching, or pressure-like pain
Worsening when the limb is elevated
Partial relief when the limb is placed in a dependent position

The positional nature of rest pain reflects critically reduced arterial inflow and diminished perfusion pressure.

Ischemic Ulceration

Ischemic ulcers in CLTI typically:

Occur on distal pressure points such as the toes, forefoot, or heel
Demonstrate poor granulation tissue formation
Heal slowly or not at all despite appropriate wound care
May be complicated by secondary infection

Inadequate tissue oxygenation impairs cellular repair mechanisms and disrupts normal wound healing cascades.

Tissue Loss and Gangrene

Advanced CLTI may progress to:

• Dry gangrene of distal digits
• Progressive tissue necrosis
• Localized or spreading tissue compromise

These findings indicate prolonged, severe perfusion deficit and loss of tissue viability.

Objective Hemodynamic Evidence

Diagnosis requires objective confirmation of arterial insufficiency, which may include:

Severely reduced ankle-brachial index
Abnormally low toe pressures
Diminished or absent pedal pulses
Imaging evidence of multilevel arterial stenosis or occlusion

CLTI is associated with high rates of limb loss and cardiovascular mortality. Prompt evaluation by a vascular specialist is essential.

Symptoms often persist despite optimized medical therapy and frequently require urgent revascularization assessment.

Chronic limb-threatening ischemia represents the most advanced stage of peripheral arterial disease and is associated with substantial limb-related and systemic risk.

Without timely revascularization and optimized medical management, ongoing hypoperfusion may result in progressive tissue compromise.

Potential complications include:

Progressive ulcer expansion and deep tissue involvement
Secondary infection, including osteomyelitis
Sepsis in severe cases
Major limb amputation
Increased risk of myocardial infarction and stroke
Elevated cardiovascular mortality

CLTI is not solely a limb disease. It reflects advanced systemic atherosclerosis and is frequently associated with diffuse vascular involvement affecting coronary and cerebrovascular territories.

Long-term outcomes are influenced by:

Degree of perfusion impairment
Presence of diabetes or renal disease
Timeliness of vascular intervention
Overall cardiovascular risk profile

Management requires coordinated, multidisciplinary care involving vascular surgery, interventional cardiology, wound care specialists, endocrinology when appropriate, and primary cardiovascular risk management.

Early recognition and structured intervention are critical to reducing limb-related and systemic complications.

Diagnosis of chronic limb-threatening ischemia requires comprehensive hemodynamic and anatomical assessment to confirm critical perfusion impairment and define revascularization options.

Evaluation typically includes:

Ankle-brachial index (ABI) to assess large-vessel perfusion pressure
Toe-brachial index (TBI) in patients with noncompressible vessels or diabetes
Duplex ultrasonography to evaluate arterial flow patterns and stenosis severity
CT angiography or MR angiography to visualize multilevel arterial disease
Conventional angiography for definitive anatomical mapping and procedural planning 

Hemodynamic testing helps quantify the severity of ischemia, while imaging identifies lesion location, length, and suitability for intervention.

Because CLTI is frequently associated with diffuse atherosclerosis, evaluation also includes systemic cardiovascular risk assessment. Patients with CLTI are at elevated risk for coronary and cerebrovascular events.

Accurate diagnostic staging is essential to guide revascularization strategy and limb preservation planning.

Management of CLTI focuses on restoring perfusion, preventing infection, and reducing systemic cardiovascular risk.

Core components of care may include:

Aggressive cardiovascular risk factor modification
Optimization of glycemic control in diabetic patients
Structured wound care and offloading strategies
Endovascular revascularization procedures such as angioplasty or stenting
Surgical bypass for suitable anatomical candidates
Infection management, including antibiotic therapy when indicated

Treatment decisions are individualized and depend on:

Vascular anatomy and lesion distribution
Degree of tissue loss
Comorbid conditions such as diabetes or renal disease
Functional status and overall surgical risk

CLTI management typically requires coordinated, multidisciplinary care involving vascular surgeons, interventional specialists, wound care teams, endocrinologists, and cardiology providers.

Timely revascularization is a key determinant of limb-related outcomes.

Hemostemix is a clinical-stage biotechnology company evaluating ACP-01, an investigational autologous cell product, in ischemic conditions including chronic limb-threatening ischemia.

ACP-01 contains angiogenic precursor cells derived from a patient’s own blood. In clinical research settings, these cells are being studied for their involvement in vascular signaling processes within ischemic tissue environments.

The company’s proposed basket protocol strategy is designed to evaluate ACP-01 across multiple ischemic conditions that share impaired perfusion as a central mechanism.

Clinical trials conducted under U.S. jurisdiction require Investigational New Drug clearance from the U.S. FDA prior to initiation. Research protocols are subject to independent ethical oversight and regulatory review.

ACP-01 is investigational and has not been approved for commercial use.