Limb Salvage in Acute Limb Ischemia and Diabetic Foot Gangrene Associated with Pancreatic Acinar Cell Carcinoma-Related Hypercoagulability

Summary

Pancreatic acinar cell carcinoma-associated hypercoagulability, combined with diabetic vasculopathy, caused acute limb ischemia and gangrene. A staged multidisciplinary limb-salvage approach achieved wound healing, preserved function, and enabled uninterrupted oncologic therapy, highlighting the importance of integrated, sequential management.

Abstract

Malignancy-associated hypercoagulability may cause arterial thrombotic events and acute limb ischemia. When combined with diabetic vasculopathy, rapid progression to gangrene and severe infection may occur.

We report a patient with type 2 diabetes who developed acute limb ischemia and progressive diabetic foot gangrene. Despite prior endovascular therapy, severe infection with necrotizing soft tissue infection and osteomyelitis developed. A staged limb-salvage approach involving aggressive debridement, removal of infected bone, pedicled flap reconstruction, antimicrobial therapy, anticoagulation, metabolic optimization, and offloading resulted in successful wound closure and functional recovery. Subsequent investigation revealed pancreatic acinar cell carcinoma, and the patient later received systemic therapy and radiofrequency ablation for liver metastasis.

This case highlights the complex interaction between advanced peripheral arterial disease, severe diabetic foot infection, and pancreatic acinar cell carcinoma (ACC)-associated hypercoagulability. Successful limb salvage was achieved through an integrated multidisciplinary strategy combining vascular intervention, aggressive surgical source control, staged reconstruction, antimicrobial therapy, anticoagulation, metabolic optimization, and oncologic management. Although causality between ACC-associated hypercoagulability and acute limb ischemia cannot be definitively established, this case demonstrates that durable wound healing and functional limb preservation can still be achieved in highly complex patients when treatment is coordinated within a staged, multidisciplinary framework.

Introduction

Diabetic foot ulcer (DFU) represents a major cause of disability and healthcare burden among individuals with diabetes. Systematic reviews estimate a global prevalence of approximately 6.3%, with a lifetime risk ranging from 19% to 34%, and recurrence after healing occurring frequently^1,2,3. From a public health perspective, DFU is associated with repeated hospitalizations, prolonged wound care, and substantial healthcare costs, as well as reduced mobility, impaired quality of life, and increased mortality. Clinically, unfavorable outcomes in DFU are typically driven by the interaction of three key factors: uncontrolled infection, inadequate tissue perfusion, and abnormal mechanical loading. In addition, chronic inflammation, impaired angiogenesis, neuropathy, and metabolic dysregulation contribute to delayed wound healing and persistent ulceration in diabetic foot disease⁴.

Current guidelines and expert consensus emphasize that the management of diabetic foot should address these three domains simultaneously. First, careful infection assessment and prompt source control are essential, including early debridement, drainage, and removal of infected bone or necrotic tissue when indicated. Second, vascular evaluation and management of peripheral arterial disease (PAD) are critical, with revascularization considered when appropriate. Third, evidence-based offloading strategies together with optimization of metabolic and cardiovascular risk factors—such as glycemic control, nutritional support, smoking cessation, lipid management, and antiplatelet therapy—should be implemented^5,6,7. In patients with moderate-to-severe infection, gangrene, or deep tissue involvement, guidelines consistently emphasize that antimicrobial therapy alone cannot substitute for surgical source control; delays in debridement and removal of infected tissue markedly increase the risk of amputation⁵. Long-term management after ulcer healing is equally important. The high recurrence rate indicates that wound closure does not necessarily imply resolution of risk. Effective offloading, appropriate footwear or orthotic support, and maintenance of normal gait mechanics and ankle dorsiflexion mobility are essential to transform short-term wound healing into durable functional outcomes⁷.

Malignancy-associated hypercoagulability, commonly referred to as the spectrum of Trousseau syndrome, may manifest as recurrent thrombotic events. In addition to venous thromboembolism, acute arterial thrombosis or embolism may also occur, potentially resulting in acute limb ischemia^8,9. Pancreatic malignancies are particularly associated with an elevated thrombotic risk. The underlying mechanisms are multifactorial and include increased tissue factor expression, inflammation-driven activation of the coagulation cascade, abnormal platelet activation, and interactions within the mucin–selectin pathway^10,11. When cancer-associated hypercoagulability coexists with diabetic atherosclerotic arterial stenosis and microvascular dysfunction, patients may develop a particularly challenging clinical scenario characterized by persistent ischemia despite revascularization and a mutually reinforcing cycle between ischemia and infection, which substantially increases the difficulty of limb salvage.

Pancreatic acinar cell carcinoma (ACC) is a rare pancreatic malignancy. Its diagnosis relies on immunohistochemical markers of acinar differentiation, such as trypsin and BCL-10, and it exhibits clinical and molecular characteristics distinct from those of pancreatic ductal adenocarcinoma^12,13. For patients complicated by severe wound infection, maintaining the continuity of oncologic therapy is equally important. If the period of open wound management overlaps with systemic cancer treatment, therapy-related bone marrow suppression and nutritional instability may increase the risk of infection recurrence and disrupt the planned oncologic treatment schedule. Therefore, when feasible, achieving early wound closure and functional recovery is clinically important to ensure the tolerability and continuity of subsequent cancer therapy. Furthermore, case-based literature in the field of complex infection and wound management provides methodological value by illustrating standardized workflows that integrate appropriate specimen collection, microbiological confirmation, and surgical source control¹⁴. In this report, we present a case of acute limb ischemia complicated by diabetic foot gangrene in the setting of ACC-associated hypercoagulability. We further discuss the potential role of malignancy-associated thrombosis in arterial events, the coordination between limb salvage and oncologic treatment timing, and strategies for the systematic management of recurrent ulceration and re-ischemia risk.

Case Presentation

A 68-year-old man with a history of type 2 diabetes mellitus, hypertension for more than 6 years, and advanced peripheral arterial disease presented with progressive right foot gangrene accompanied by severe infection and ischemic deterioration. His medical history was significant for lower-extremity arterial occlusive disease requiring catheter-directed thrombolysis and right tibial artery balloon angioplasty. The patient denied smoking and alcohol consumption. During the month preceding admission, he experienced progressive deterioration of the right foot wound associated with pain, tissue necrosis, and impaired ambulation, accompanied by an unintentional weight loss of approximately 5 kg. On admission, the right foot showed marked cyanosis and decreased skin temperature, with weakened or absent distal arterial pulses. Progressive swelling and exudation subsequently developed, and gangrene gradually formed with extension into deeper tissues.

Diagnosis, Assessment, and Plan

The clinical presentation was consistent with necrotizing soft tissue infection, characterized by severe pain and swelling, skin discoloration, increased local tissue tension, and purulent discharge. Laboratory tests indicated significant inflammatory activity. The white blood cell count reached a peak of approximately 17.98 × 10⁹/L, with neutrophils accounting for about 94%. High-sensitivity C-reactive protein (hsCRP) exceeded 200 mg/L, and procalcitonin was approximately 0.16 ng/mL. The infection extended beyond a superficial diabetic ulcer and was complicated by forefoot gangrene, necrotizing fasciitis, metatarsal osteomyelitis, and phalangeal osteomyelitis. Microbiological cultures obtained from wound exudate yielded Staphylococcus simulans. Antimicrobial susceptibility testing demonstrated susceptibility to oxacillin, vancomycin, linezolid, levofloxacin, clindamycin, and trimethoprim–sulfamethoxazole, without evidence of methicillin resistance. Coagulation parameters suggested a hypercoagulable state, with D-dimer levels of 1050 µg/L FEU and fibrinogen levels of 8.77 g/L. Additional coagulation tests revealed an activated partial thromboplastin time (APTT) of 49.1 s, thrombin time (TT) of 20.1 s, and an international normalized ratio (INR) of 1.24 (Table 1). Computed tomography angiography (CTA) of the lower extremities demonstrated extensive atherosclerotic disease involving the bilateral lower extremity arteries, with diffuse calcific plaques affecting the abdominal aorta, common iliac arteries, and external iliac arteries. A soft plaque was identified in the proximal segment of the right profunda femoris artery, resulting in severe luminal stenosis, while additional moderate stenotic lesions were present in distal arterial segments. These findings indicated advanced peripheral arterial disease and provided a significant anatomical substrate for the development of acute limb ischemia. In addition, pancreatic imaging revealed a space-occupying lesion in the pancreatic head suspicious for malignancy, which was subsequently confirmed as pancreatic acinar cell carcinoma (ACC) by biopsy (Figure 1).

An integrated multidisciplinary strategy combining vascular intervention, aggressive surgical source control, staged reconstruction, antimicrobial therapy, anticoagulation, metabolic optimization, and oncologic management was planned.

Protocol

This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the First Affiliated Hospital, Zhejiang University School of Medicine. Written informed consent was obtained from the patient for participation and publication of clinical data and images. All clinical procedures, including surgical intervention, specimen handling, and imaging acquisition, were performed in accordance with institutional standards and national clinical practice guidelines.

1. Initial clinical assessment

1. Patient history
   1. A comprehensive clinical history was obtained, with particular emphasis on the duration and progression of symptoms, including acute onset of limb pain, numbness, cyanosis, and progressive tissue necrosis.
   2. Relevant comorbidities such as type 2 diabetes mellitus, cardiovascular risk factors, prior vascular interventions (including thrombolysis and angioplasty), and medication history were documented.
   3. Additional attention was given to risk factors for hypercoagulability, including unexplained thrombotic events and potential malignancy-associated features.
2. Physical examination
   1. A detailed physical examination of the affected limb was performed, including assessment of skin temperature, color changes, capillary refill, presence of cyanosis or gangrene, tissue tension, edema, exudation, and signs of deep infection.
   2. Palpation of distal pulses and evaluation of sensory and motor function were conducted. Clinical signs suggestive of necrotizing soft tissue infection—such as disproportionate pain, rapid progression, skin discoloration, and purulent discharge—were carefully evaluated.
   3. Systemic examination was performed to assess signs of sepsis or organ dysfunction.

2. Imaging studies

1. Lower-extremity computed tomography angiography (CTA)
   1. CTA of the lower extremities was performed using a multi-detector CT system to evaluate arterial patency and identify stenotic or occlusive lesions.
   2. The patient was positioned supine, and scanning was conducted from the abdominal aorta to the distal pedal arteries.
   3. Typical parameters included 120 kVp, 200–300 mAs with automatic exposure control, collimation of 0.6–1.0 mm, pitch of 1.0–1.2, and slice thickness of 1 mm.
   4. Intravenous contrast (non-ionic iodinated agent, 1.2–1.5 mL/kg) was administered at 3–4 mL/s via an antecubital vein, with arterial phase acquisition using bolus tracking.
   5. Images were reconstructed in axial, coronal, and sagittal planes to assess arterial stenosis, plaque morphology, and distal perfusion.
2. Local limb imaging
   1. Where indicated, plain radiographs or CT imaging of the affected foot were obtained to evaluate bone involvement, including osteolysis, cortical destruction, and joint involvement suggestive of osteomyelitis.
   2. Imaging fields included the forefoot and midfoot regions with appropriate positioning to visualize soft tissue swelling and gas formation if present.
3. Abdominal imaging for malignancy screening
   1. Cross-sectional imaging of the abdomen (contrast-enhanced CT or MRI) was performed to investigate potential malignancy in the context of unexplained hypercoagulability.
   2. Scanning covered the pancreas and hepatobiliary system. For contrast-enhanced CT, parameters included 120 kVp, 250–300 mAs, with portal venous phase acquisition at 70–80 seconds following administration of iodinated contrast (1.5 mL/kg).
   3. Imaging findings suggestive of pancreatic neoplasm were further evaluated.

3. Laboratory and diagnostic tests

1. Hematological and inflammatory markers
   1. Peripheral blood samples were collected to evaluate systemic inflammation and infection severity, including white blood cell (WBC) count, differential count, hsCRP, and procalcitonin.
   2. These markers were monitored serially to assess disease progression and response to treatment.
2. Coagulation profile
   1. A comprehensive coagulation panel was obtained, including D-dimer, fibrinogen, activated partial thromboplastin time (APTT), thrombin time (TT), and international normalized ratio (INR), to assess hypercoagulability and guide antithrombotic therapy.
   2. Elevated D-dimer and fibrinogen levels were interpreted in the context of malignancy-associated thrombotic risk.
3. Microbiological assessment
   1. Intraoperative tissue specimens and wound exudates were collected under sterile conditions for microbiological culture.
   2. Samples were placed in sterile containers without fixative and transported promptly to the microbiology laboratory. Cultures for aerobic and anaerobic bacteria, as well as fungal pathogens, were performed.
   3. When osteomyelitis was suspected, bone specimens were preferentially obtained for culture and sensitivity testing.
4. Histopathological examination
   1. Debrided soft tissue and bone specimens were fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned at 4 µm, and stained with hematoxylin and eosin.
   2. Histological evaluation focused on necrosis, inflammatory infiltration, vascular changes, and confirmation of osteomyelitis.
5. Oncologic diagnosis
   1. Biopsy of the pancreatic lesion was performed under image guidance. Immunohistochemical staining included markers of acinar differentiation (trypsin, BCL-10) and neuroendocrine markers (chromogranin A, synaptophysin), along with Ki-67 proliferation index.
   2. These findings were used to confirm the diagnosis of pancreatic acinar cell carcinoma.

4. Diagnostic assessment

1. Acute/subacute limb ischemia
   1. The patient initially presented with an acute onset of distal limb pain, numbness, cyanosis, and decreased skin temperature, all suggestive of limb ischemia.
   2. Clinical improvement after endovascular recanalization performed at another hospital was limited, indicating persistent perfusion compromise.
   3. Computed tomography angiography (CTA) revealed significant atherosclerotic disease with severe arterial stenosis, providing an anatomical basis for the ischemic event.
   4. Taken together with the clinical manifestations and disease course, these findings were consistent with an acute or subacute ischemic event occurring on the background of structural arterial disease.
2. Severe diabetic foot infection (necrotizing fasciitis and osteomyelitis)
   1. The presence of local gangrene, clinical signs of deep soft tissue infection, and intraoperative findings were observed, indicating extensive tissue involvement.
   2. The diagnostic framework included necrotizing fasciitis and osteomyelitis involving the toes and metatarsal bones. These findings suggested that antimicrobial therapy alone would be insufficient and that aggressive surgical intervention focusing on infection source control was required.
3. Pancreatic acinar cell carcinoma (ACC)
   1. A pancreatic mass was confirmed as pancreatic acinar cell carcinoma (ACC) by biopsy.
   2. Immunohistochemical analysis demonstrated positive staining for acinar differentiation markers (trypsin and BCL-10) and negative staining for neuroendocrine markers (chromogranin A and synaptophysin).
   3. The proliferation index was markedly elevated, with Ki-67 positivity of approximately 70%, supporting the diagnosis of highly proliferative ACC and indicating aggressive biological behavior.
4. Analysis of arterial thrombotic factors
   1. In this case, clear arterial stenosis was observed, suggesting that the ischemic event should not be attributed solely to malignancy-associated hypercoagulability.
      NOTE: A more comprehensive interpretation is that the underlying arterial stenosis provided the anatomical substrate for ischemia, while ACC-associated hypercoagulability likely acted as a triggering or amplifying factor. This prothrombotic state may have increased the tendency for thrombosis and recurrence, rendering the ischemia more refractory and accelerating the pathological cascade of ischemia, infection, and tissue necrosis.

5. Therapeutic intervention

1. Overall management strategy
   1. The overall management strategy was planned around four key principles: prioritizing infection source control, staged limb-salvage reconstruction, continuous antimicrobial and antithrombotic therapy, and metabolic optimization with biomechanical offloading.
   2. After confirmation of the oncologic diagnosis, multidisciplinary oncologic management was subsequently incorporated.
2. Surgical management
   1. A staged limb-salvage surgical strategy was adopted (Figure 2).
   2. First-stage surgery:
      1. Radical debridement was performed to remove extensive necrotic soft tissue, devitalized tendons, and infected bone.
      2. Intraoperative findings confirmed necrotizing fasciitis with metatarsal and phalangeal osteomyelitis. The involved metatarsal and phalangeal bone segments were excised until viable tissue margins were achieved.
      3. Following extensive irrigation, a pedicled fascial flap was rotated to cover exposed bone surfaces, and an additional pedicled flap was used to reconstruct the plantar soft-tissue defect.
      4. Antibiotic-loaded bone cement was applied to residual high-risk areas, and multiple drainage tubes were placed for postoperative infection control.
   3. Second-stage surgery:
      1. After infection control and wound stabilization had been achieved, a second-stage reconstructive procedure was performed.
      2. Residual chronic ulcerative tissue was excised, synovectomy of the foot and toe joints was undertaken when necessary, and additional pedicled fascial flap reconstruction was performed to reinforce soft-tissue coverage.
      3. Drainage management and wound conditioning were optimized to facilitate definitive wound healing and functional limb preservation.
3. Antimicrobial therapy
   1. Antimicrobial therapy followed the principle of “source control first, antibiotics as adjunctive treatment.” On the basis of surgical debridement and drainage, broad-spectrum antimicrobial therapy was initiated and subsequently adjusted according to microbiological findings and antimicrobial susceptibility testing.
   2. Wound cultures yielded Staphylococcus simulans, which demonstrated susceptibility to oxacillin, vancomycin, linezolid, levofloxacin, clindamycin, and trimethoprim–sulfamethoxazole (Table 2).
   3. Serial monitoring of inflammatory markers, wound appearance, drainage characteristics, and clinical response was used for guided antimicrobial optimization throughout treatment.
4. Anticoagulation and perfusion management
   1. Given the presence of ischemic manifestations and the increased thrombotic risk associated with malignancy, anticoagulation and antithrombotic therapy were implemented throughout treatment.
   2. Low-molecular-weight heparin (nadroparin calcium, 4100 IU subcutaneously once daily) was administered as the principal anticoagulant agent.
   3. In addition, oral sarpogrelate and beraprost sodium were prescribed to reduce thrombotic risk and improve peripheral circulation.
   4. Coagulation parameters, D-dimer levels, bleeding events, and distal limb perfusion were monitored regularly during hospitalization and follow-up.
   5. Particular attention was paid to preventing recurrent ischemia that could compromise flap viability, delay wound healing, or result in recurrent tissue necrosis.
5. Metabolic optimization and rehabilitation
   1. Strict glycemic control and correction of nutritional risk factors were maintained throughout treatment.
   2. Once the wound entered a stable phase, evidence-based offloading strategies and gait training were introduced to reduce focal pressure on the residual limb and prevent the cycle of callus formation, ulceration, and reinfection.
   3. Maintenance of ankle dorsiflexion mobility and appropriate biomechanical alignment during ambulation was also emphasized.

6. Follow-up

1. After wound healing, the patient proceeded to systemic treatment for pancreatic acinar cell carcinoma (ACC). During follow-up, hepatic metastases were identified and managed with ultrasound-guided radiofrequency ablation, with procedures repeated as required based on disease progression.
2. The patient remained clinically stable throughout follow-up. No evidence of recurrent limb infection, recurrent ulceration, wound breakdown, progressive tissue necrosis, or recurrent ischemic events was observed.
3. No additional limb-related surgical intervention was required.
4. Successful limb preservation was maintained while the patient proceeded with subsequent oncologic management, including systemic therapy and radiofrequency ablation of hepatic metastases.
   NOTE: These findings underscore the clinical importance of achieving early wound closure and functional restoration in patients with limb-threatening infections, particularly in those requiring intensive cancer treatment.

Results

The patient ultimately achieved successful limb salvage without the need for major amputation (Figure 3). The wound progressively stabilized and reached complete closure. At the latest follow-up, 5 months after the final reconstructive procedure, durable wound healing had been achieved with stable soft-tissue coverage and restoration of the skin barrier (Figure 3). The patient regained independent standing and ambulation without the need for assistive devices. I...

Discussion

DFU represents a major and persistent burden at the population level. A systematic review estimated the global prevalence to be approximately 6.3%¹. Other large reviews suggest that the lifetime risk of foot ulceration in patients with diabetes may reach 19–34%, and recurrence after healing is common, often leading to infection, hospitalization, and amputation^2,3. These observations underscore that diabetic foot care is not a single ...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Adobe Illustrator	Adobe Inc. (San Jose, CA, USA)	Illustrator 2024	Figure preparation
Aerobic Culture Medium	BD Diagnostics (Franklin Lakes, NJ, USA)	https://www.bd.com/en-in/products-and-solutions/solutions/capabilities/bd-bactec-blood-culture-media	Bacterial culture
Anaerobic Culture Medium	BD Diagnostics (Franklin Lakes, NJ, USA)	https://www.bd.com/en-in/products-and-solutions/solutions/capabilities/bd-bactec-blood-culture-media	Anaerobic bacterial culture
Antibiotic-loaded Bone Cement	Heraeus Medical (Wehrheim, Germany)	PALACOS R+G	Temporary local antibiotic delivery
BCL-10 Antibody	Abcam (Cambridge, UK)	ab33994	Immunohistochemical marker for ACC; Dilution as per the manufacturer's guidelines
Beraprost Sodium Tablets	Toray Industries (Tokyo, Japan)	Dorner	Peripheral circulation improvement
Chromogranin A Antibody	Dako (Glostrup, Denmark)	M0869	Neuroendocrine marker; Dilution as per the manufacturer's guidelines
Formalin Solution (10%)	Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China)	N/A	Tissue fixation
Hematoxylin and Eosin Staining Kit	Solarbio (Beijing, China)	G1120	Histopathological evaluation
Ki-67 Antibody	Dako (Glostrup, Denmark)	M7240	Proliferation index assessment
Linezolid Tablets	Pfizer (New York, NY, USA)	Zyvox	Antimicrobial therapy
Magnetic Resonance Imaging System	GE Healthcare (Chicago, IL, USA)	Discovery Series	Used for pancreatic imaging
Multi-detector CT Scanner	Siemens Healthineers (Erlangen, Germany)	Somatom Series	Used for lower-extremity CTA
Nadroparin Calcium Injection	Aspen Pharma (Dublin, Ireland)	Fraxiparine	Anticoagulation
Nonionic Iodinated Contrast Agent	Bayer Healthcare (Leverkusen, Germany)	Ultravist 370	CTA contrast medium
Pedicled Fascial Flap Technique	N/A	N/A	Surgical reconstruction technique
Piperacillin/Tazobactam	Pfizer (New York, NY, USA)	Zosyn	Antimicrobial therapy
Sarpogrelate Hydrochloride Tablets	Mitsubishi Tanabe Pharma (Osaka, Japan)	N/A	Antiplatelet therapy
Statistical Analysis Software	IBM Corp. (Armonk, NY, USA)	SPSS Version 26.0	Data analysis (if applicable)
Surgical Drainage Tube	B. Braun (Melsungen, Germany)	https://catalogs.bbraun.com/en-01/c/PRODUCTS/b-braun-standard-product-catalog	Postoperative drainage
Synaptophysin Antibody	Dako (Glostrup, Denmark)	M0776	Neuroendocrine marker; Dilution as per the manufacturer's guidelines
Trypsin Antibody	Abcam (Cambridge, UK)	ab200997	Immunohistochemical marker for ACC; Dilution as per the manufacturer's guidelines
VITEK 2 Compact System	bioMérieux (Marcy-l'Étoile, France)	https://www.biomerieux.com/corp/en/our-offer/clinical-products/vitek-2-compact.html	Bacterial identification and susceptibility testing