Persistent hypercoagulability and acute limb ischemia post COVID-19

Abstract

Research indicates that COVID-19 induces endotheliitis, hypercoagulation, and hypofibrinolysis owing to virus-induced endothelial dysfunction. We present a case of a 34-year-old man with acute limb ischemia 4 days after COVID-19 diagnosis. Arterial duplex ultrasound examination revealed acute thrombosis of the popliteal artery and systemic anticoagulation was started. Despite multiple successful embolectomies and aggressive anticoagulant therapy, rethrombosis occurred, requiring bypass surgery approximately 1 year later. This case highlights the prolonged hypercoagulability post COVID-19 infection and the need for ongoing monitoring and tailored thromboprophylaxis to manage complications, especially with the evolving understanding of COVID-19-related hypercoagulability.

Hypercoagulability, defined as an increased thrombus formation risk, is marked by unprovoked thrombus and/or decreased fribrinolysis.¹ It may be inherited or acquired, with overlapping risk factors.^2,3 Emerging evidence suggests thrombosis results from a complex interaction between genetic predispositions and environmental triggers.^4,5 Acquired factors include surgery, pregnancy, hormone therapy, malignancy, inflammation, infections, and heparin-induced thrombocytopenia.⁶

Recent research has highlighted the strong association between COVID-19 and elevated thrombotic risk, even with in-hospital thromboprophylaxis.^7,8 Venous thromboembolism is a major complication of COVID-19, although outpatient data remain limited.⁹ COVID-19-associated coagulopathy involves increased thrombin generation, early-phase thrombocytosis, late-phase thrombocytopenia, impaired fibrinolysis, and elevated D-dimer levels. These features have been demonstrated by coagulation tests, viscoelastic testing, and markers of thrombin/fibrin generation, platelet activation, and fibrinolysis.¹⁰

Although initially classified as a respiratory illness, COVID-19 generates a unique prothrombotic state. Thrombosis begins in the pulmonary vasculature, progressing systemically.¹¹ Long-term consequences of COVID-19-associated coagulopathy remain unclear, with limited research on persistent hemostatic abnormalities post recovery. The patient provided informed consent for publication of case details and images.

Case report

A 34-year-old man with morbid obesity, diabetes, and hypertension presented with acute pain and left leg discoloration in March 2021. He tested positive for COVID-19 4 days earlier and received monoclonal antibody treatment 2 days prior. There was no history of atherosclerosis, hypercoagulability, arrhythmia, or prior limb ischemia. Hypercoagulability workup was completed. No lupus anticoagulant was detected, antithrombin activity was normal, and the patient was negative for phospholipid-dependent screening and factor V Leiden test. Physical examination revealed a cold, pale left leg with absent posterior tibial (PT) and dorsalis pedis pulses, with decreased sensation and absent motor function. Arterial duplex imaging indicated left popliteal artery thrombosis. He was administered systemic heparin therapy and taken to the operating room with interventional radiology. Angiogram revealed occlusion of the left popliteal, anterior tibial (AT), PT, and peroneal arteries (Fig 1).

Fig 1.

Arteriogram revealing left popliteal artery thrombus extending down to the anterior tibial (AT) artery and the tibioperoneal (TP) trunk.

Catheter-directed thrombolysis with 5 mg tissue plasminogen activator (TPA) and percutaneous thrombectomy using an Angiojet were performed. The angiographic result was poor, and the patient lacked pulses post procedure. Platelet count at this time was 298; heparin-induced thrombocytopenia panel was sent later and was negative. Vascular surgery was consulted intraoperatively, and the patient underwent open wire-guided Fogarty thromboembolectomy with good clearance of all three tibial vessels. A four-compartment fasciotomy was performed owing to prolonged ischemia. An aortogram during this procedure showed thrombus in the common iliac artery, and a Viabahn (W. L. Gore & Associates) self-expanding covered stent was deployed to exclude the thrombus (Fig 2). A completion arteriogram showed resolution of the thrombus at the left common iliac artery and restoration of flow to AT, PT, and peroneal arteries (Fig 3). Postoperatively, left dorsalis pedis and PT pulses were palpable, with intact sensation and motor function.

Fig 2.

Intraoperative arteriogram revealing a free-floating thrombus within the left common iliac artery.

Fig 3.

Completion arteriogram restored flow to the anterior tibial (AT), posterior tibial (PT), and peroneal arteries.

Six hours after the operation, the patient lost pulses and Doppler signals in the left foot despite systemic heparin and clopidogrel. Bivalirudin and tirofiban infusions were added, and the patient underwent an aortogram and thromboembolectomy. The arteriogram showed occlusion of the left common iliac artery stent, left common femoral artery, and reocclusion of the popliteal artery down to the tibioperoneal (TP) trunk. A left femoral artery cutdown with Fogarty thromboembolectomy and local TPA infusion restored perfusion and pedal pulses.

Patient's presumption of COVID-19-induced hypercoagulability led to the administration of a postoperative regimen of heparin, bivalirudin, tirofiban, clopidogrel, and aspirin. On day 7, he switched to apixaban, clopidogrel, and aspirin. He was discharged on day 16 to rehabilitation with clopidogrel (75 mg) and apixaban (5 mg) and weekly follow-ups for fasciotomy wound management. Hematology was on board throughout his admission and provided additional recommendations regarding anticoagulation. Thromboelastography and clopidogrel (Plavix) resistance testing were not sent at this time.

Six months after the original procedure, in November 2021, the patient presented with occlusion of the common left iliac artery stent and tibial artery. Catheter-directed thrombolysis and percutaneous mechanical thrombectomy restored perfusion to the PT artery, but the AT and peroneal arteries remained occluded. The limb remained functional with intact neurovascular status.

In October 2022, the patient returned with worsening calf pain after stopping anticoagulation owing to financial constraints. Angiography revealed occlusion of the left common iliac and popliteal arteries. Percutaneous thrombectomy was performed on the popliteal and proximal AT arteries, with distal occlusion at the AT takeoff and TP trunk. AngioJet thrombectomy was done at the distal popliteal artery, PT artery, and TP trunk, with 6 mL of TPA infused locally. A completion arteriogram showed resolution of the clot in the popliteal and PT arteries. An EKOS thrombolysis catheter (Boston Scientific) was placed in the left CFA, with TPA lysis. Continuous heparin started to prevent rethrombosis.

The following day, the left common iliac artery was patent with minimal clot, but the left popliteal, AT, and PT arteries reoccluded, requiring a lytic catheter and AngioJet thrombectomy. After thrombus removal, the patient developed severe calf pain and compartment syndrome, necessitating fasciotomy. Four days later, repeated ischemic limb and absent foot signals prompted consideration of a femoral-to-PT bypass or amputation. The patient chose the bypass using the contralateral greater saphenous vein. A popliteal-to-distal PT bypass was completed without incident, and the completion arteriogram showed excellent flow to the foot.

Postoperatively, the patient required additional fasciotomy wound management, debridement, and prolonged vacuum-assisted closure before achieving closure by secondary intention. Despite recurring ischemia, he reported no pain or mobility issues and intact neurovascular function. In June 2023, the PT pulse was palpable, the wounds healed, and no graft stenosis was present. He was on clopidogrel 75 mg and apixaban 5 mg. By April 2025, he walked without a cane after extensive physical therapy.

Discussion

Post-COVID-19 patients, especially those with cardiovascular risk factors, face a high risk of arterial and venous thrombosis. COVID-19-associated coagulopathy leads to hypercoagulability and endothelial dysfunction, contributing to macrovascular and microvascular complications that can persist for up to 1 year, regardless of symptom severity.¹² This result highlights the importance of duplex monitoring, thromboprophylaxis, and long-term anticoagulation for patients with thrombotic events within a year of diagnosis. Additional work-up with thromboelastography and clopidogrel resistance testing may help in recurrent cases. A systematic review found thromboelastography useful in identifying post-COVID-19 hypercoagulability.¹³

This case highlights persistent hypercoagulability beyond acute infection. Our patient experienced multiple thrombotic events despite technically successful thrombectomy and anticoagulation. Such recurrences, especially after brief interruption of anticoagulation, was common during the pandemic and reflects underappreciated long-term risk. Initial laboratory tests include prothrombin time, partial thromboplastin time, complete blood count, C-reactive protein, anticardiolipin antibody, antithrombin, and protein C/S, factor VIII, fibrinogen, prothrombin 20210A, antiphospholipid antibody, and homocysteine.¹⁴ Hematology input and laboratory monitoring help to guide anticoagulant response.

Evidence for long-term anticoagulation post COVID remains limited. Studies on extended thromboprophylaxis are mixed, possibly owing to postinfection heparin resistance.¹⁵ Additional follow-up is needed, and lifelong anticoagulation should be considered, because recurrence may lead to disability or limb loss.

Conclusions

This case highlights the persistence of hypercoagulability in a COVID-19-negative patient with continued severe vascular complications more than 1 year after initial infection. The need for complex interventions, including bypass surgery in a young adult, underscores the necessity for deeper insight into the resistance to treatment associated with hypercoagulability. Developing standardized guidelines for anticoagulation and monitoring will be crucial in addressing the appropriate prophylaxis treatment for these patients.

Funding

None.

Disclosures

None.