The Swollen Calf of Reperfusion Injury

Unilateral calf pain and swelling are suggestive of deep vein thrombosis (DVT) but may also result from muscle or tendon tear, Baker's cyst, soft tissue infection, and inflammation. ^{1 2 3} To distinguish mimickers from DVT, the term pseudothrombophlebitis is used, meant to avoid potential harm from anticoagulant treatment, and foster disease-specific management. We describe pseudothrombophlebitis in the followings of iliac artery thrombosis, thromboendarterectomy, and rhabdomyolysis of calf muscles. Awareness to this rare occurrence is warranted.

Case History

An 80-year-old man underwent laparoscopic nephrectomy for left renal cell carcinoma. The following morning his left leg felt cold and the femoral artery pulse was not perceived. Computer tomography angiography showed occlusion of the left common iliac artery. Thromboendarterectomy was done in emergency, whereupon the femoral and distal pulses were back to normal. At this point the creatine kinase was >100.000 U/L (reference range 22–198 U/L). The rapid rise of serum creatine kinase to >10 times reference range was consistent with rhabdomyolysis. ⁴ Concurrently, the serum creatinine rise to 2.6 mg/dL was consistent with acute renal failure. Dual antiplatelet therapy with aspirin and clopidogrel was started along with intravenous hydration. The patient's general condition improved. On the sixth postoperative day, left calf became heavily swollen without pitting edema, ecchymoses, erythema, and venectasia. Doppler ultrasonography showed normal flow in the popliteal and femoral veins. At this time the serum creatine kinase had returned to normal levels. One week after the first vascular imaging the venous ultrasound examination was repeated, again showing normal flow in the leg veins, no popliteal cyst or mass, no calf hematoma. For now, the swelling of the left calf had resolved. The patient's clinical status continued to improve, he regained leg muscle strength, was ambulatory, and examination of the legs was unremarkable. The patient's medical history was notable for pulmonary embolism 6 months before the present admission, and transitional cell carcinoma of the bladder. He had recently undergone transurethral resection of the bladder tumor. Anticoagulant had been temporarily discontinued. In the given context, a paraneoplastic hypercoagulability state was highly probable. ^{5 6} Anticoagulant prophylaxis with apixaban was resumed. Oncology treatment was scheduled.

Discussion

Distinguishing DVT from its mimickers, such as Baker's cyst, muscle or tendon tear, soft tissue infection, and inflammation is straightforward. ^{1 2 3} Familiarity with these conditions and their sonographic findings are useful in making timely and correct diagnosis. ⁷ None of the common causes of pseudothrombophlebitis were involved in the propósito. The temporal sequence of the events—laparoscopic surgery, iliac artery thrombosis, successful reperfusion, followed by reperfusion injury (as supported by rhabdomyolysis and acute renal failure), and a few days later the swelling of the ipsilateral calf—were consistent with ischemia-reperfusion injury. ⁸ Obstruction of arterial blood flow causes tissue hypoxia and leads to profound dysfunction of the mitochondria, resulting in decreased production of ATP that no longer meets the metabolic needs of the cell. Under anaerobic metabolism there is dysfunction of the sodium-potassium pumps. Hydrogen, sodium, and calcium ions accumulate in the cells causing hyperosmolarity, water inflow to the cytoplasm, cell swelling, activation of phospholipases, proteases, and long lasting damage to the cell membrane. Mitochondrial injury also contributes to the accumulation of reactive oxygen species. Restoration of the blood flow provides oxygen to ischemic tissues. Due to low levels of antioxidants in the ischemic cells, the generation of reactive oxygen species increases. Reactive oxygen species promote endothelial dysfunction, DNA damage, and local inflammatory cascades which may further damage the cellular structures. ⁸ In as little as two 2 hours ischemia-reperfusion may cause muscle damage; within 4 hours irreversible anatomical and functional changes may evolve, i.e., rhabdomyolysis. Massive muscle breakdown releases large amounts of cellular compounds into the bloodstream. A rapid rise in serum creatine kinase typically occurs to more than 10 times reference range, followed by a rapid decrease. This is confirmatory for the diagnosis of rhabdomyolysis ^{4 9} and such was witnessed in the propósito. The cause of tissue ischemia in the propósito was acute occlusion of the left common iliac artery. Re-opening of the artery was followed by swelling of the ipsilateral calf. Indeed, after surgical revascularization, profound edema of the muscles in the involved extremity may occur due to massive fluid extravasation and inflammatory reactions. ¹⁰ Limb swelling due to ischemia-reperfusion injury may simulate DVT. When extensive, exudation in the calf compartment may produce high tissue pressure and compartment syndrome. Compartment syndrome secondary to thrombosis of the common iliac artery has been described after pelvic surgery performed in the “exaggerated lithotomy position.” ^{11 12} Although providing good exposure for urethral and prostatic surgery, the exaggerated lithotomy position is associated with a low but definite risk of rhabdomyolysis, compartmental syndrome, neurapraxia, and acute renal failure. In the propósito, timely diagnosis of iliac artery thrombosis and restoration of the arterial blood flow prevented the development of compartment syndrome. However, it could not avert tissue damage in the distal leg. The latter was marked by massive release of muscle enzymes and swelling of the deep calf tissues, diagnosed by the physicians as pseudothrombophlebitis. Among etiologies of pseudothrombophlebitis, reperfusion injury is not mentioned in textbooks and devoted reviews. It is an important distinction to be made. Awareness to this rare occurrence is warranted.