British Journal of Radiology 75 (2002),843-846 © 2002 The British Institute of Radiology
Peripheral arterial insufficiency associated with protein C deficiency
Y P Cho, MD
1
D H Lee, MD
2
H J Jang, MD
1
J S Kim, MD
1
M S Han, MD
1 and
S G Lee, MD
3
Departments of 1 General Surgery and 2 Diagnostic Radiology, Asan Kangnung Hospital, 415 Bangdong Ri, Sachun Myun, Kangnung and 3 Department of General Surgery, University of Ulsan Medical College and Asan Medical Center, 388-1 Poongnap Dong, Songpa Ku, Seoul, Republic of Korea
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Abstract
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Two patients with protein C deficiency who presented with peripheral arterial insufficiency were successfully managed. One patient was managed with bypass surgery for focal gangrene followed by full anticoagulation whilst the other patient was managed with full anticoagulation. Both patients showed characteristic arteriographic findings. Patients who present with peripheral arterial insufficiency demonstrating thrombotic occlusion of main peripheral artery without atherosclerosis and other risk factors should be evaluated for hypercoagulable states.
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Introduction
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There are a number of conditions that can lead to a hypercoagulable state. Protein C and protein S deficiencies are frequently described as causes of hypercoagulable states. Although protein C and protein S deficiencies have frequently been associated with venous thromboembolic events, instances of arterial thromboses have been reported, especially in young patients [1–4]. The exact incidence of protein C and protein S deficiencies in patients with peripheral arterial insufficiency has not been established. Given the lack of adequate studies to define the natural history and arteriographic findings of these patients, treatment has not been well delineated.
We report two patients who presented with peripheral arterial insufficiency and characteristic arteriographic findings in association with protein C deficiency.
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Case 1
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A 35-year-old male patient was admitted to hospital because of recently aggravated rest pain in the right calf of 5 months duration and gangrene of the right first toe of 15 days duration. The patient had smoked 20 cigarettes daily for the past 20 years. No other risk factors were identified. Clinical examination revealed no palpable pulses from the right femoral and pedal arteries. Left peripheral pulses were palpated normally. Apart from slight elevation of the white blood cell count (10 000 µl-1), blood chemistry parameters were unremarkable. Segmental leg pressure test showed a decreased ankle–brachial pressure ratio of the right leg (0.28) with a pressure gradient at the level of the iliac (55 mmHg) and popliteal (40 mmHg) arteries. Femoral arteriography demonstrated complete obstruction of the right external iliac artery, without visualization of the common, superficial femoral or popliteal arteries, as well as the upper two-thirds of lower leg vessels (Figure 1a
). The aorta and other arteries showed normal anatomy and luminal patency without evidence of atherosclerosis. Hypercoagulability studies were performed before operation. Antigenic protein C level was 55% of normal, but other parameters were all unremarkable. Initially, common-iliac-artery–deep-femoral-artery bypass with 10 mm polytetrafluoroethylene (PTFE) and profundoplasty was performed. Full anticoagulation, with heparin followed by warfarin, was carried out immediately after operation. Rest pain was improved, and ankle–brachial pressure ratio was increased to 0.48. Gangrene of the right first toe was managed conservatively for the subsequent 2 months but did not improve. Composite sequential bypass using 6 mm PTFE from the initial distal bypass graft (10 mm PTFE) to above the knee, with in situ saphenous vein placed between the 6 mm PTFE and the distal posterior tibial artery, was performed. Post-operative arteriography showed good patency of the bypass graft between the graft and posterior tibial artery (Figure 1b), and gangrene of the right first toe healed well. The patient has continued to do well with anticoagulant therapy for 8 months.
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Figure 1. Femoral arteriographic findings in case 1. (a) Pre-operative arteriography showed complete obstruction of the right external iliac artery, without visualization of common, superficial femoral or popliteal arteries, as well as the upper two-thirds of lower leg vessels. (b) Post-operative arteriography showed good patency of the bypass graft. White arrows, 10 mm polytetrafluoroethylene (PTFE); black arrows, 6 mm PTFE; open arrows, in situ saphenous vein; black arrowheads, anastomotic site between 6 mm PTFE and saphenous vein; open arrowhead, anastomotic site between saphenous vein and posterior tibial artery.
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Case 2
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A 65-year-old male patient was admitted to hospital because of sudden onset of generalized tonic-clonic seizure. Apart from right leg claudication for 1 year, past history and family history were not remarkable. No risk factors were identified. Clinical examination revealed no palpable pulses from the right pedal arteries. Left peripheral pulses were palpated normally. Blood chemistry parameters were all unremarkable. Brain CT showed left parietal subcortical intracerebral haemorrhage. Transfemoral cerebral arteriography and femoral arteriography demonstrated partial thrombosis of the anterior half of the superior sagittal sinus and complete obliteration of the right superficial femoral and distal run-off arteries with well-developed collateral circulation from the deep femoral artery (Figure 2). The aorta and other arteries showed normal anatomy and luminal patency without evidence of atherosclerosis. Segmental leg pressure test showed decreased ankle–brachial pressure ratio of the right leg (0.69) with a pressure gradient at the level of the femoral artery (30 mmHg). Hypercoagulability studies were performed. Antigenic protein C and antigenic protein S levels were 35% and 46%, respectively, of normal. Full anticoagulation, with heparin followed by warfarin, was initiated. The patient has continued to do well with anticoagulant therapy for 5 months.
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Figure 2. In case 2, femoral arteriography showed complete obliteration of the right superficial femoral and distal run-off arteries with well developed collateral circulation from the deep femoral artery (the view at the level of the distal femur is not included).
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Discussion
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The term "hypercoagulable state" is generally used to denote any condition in which the normal balance between clotting and anticlotting mechanisms becomes altered in such a way that the patient is predisposed to thrombus formation [5]. There are a number of conditions that can lead to a hypercoagulable state. Protein C and protein S deficiencies are frequently described as causes of hypercoagulable states [1–4, 6, 7]. Protein C and protein S are two of the vitamin K dependent proteins. Activated protein C (protein Ca) inactivates factors Va and VIIIa. Protein C activation to protein Ca through the interaction of thrombomodulin and thrombin on the endothelial cell surface occurs 20 000 times faster than by thrombin alone [8]. In addition, protein C proteolytically inactivates the tissue plasminogen activator inhibitor, thus increasing the natural fibrinolytic activity of plasma. Protein S is a cofactor for protein C. The activity of protein Ca is increased several orders of magnitude by its non-enzymatic cofactor protein S. Protein C and protein S deficiencies may be seen in both congenital and acquired forms. They are inherited in an autosomal dominant manner. In congenital conditions, those individuals homozygous for protein C deficiency usually die in infancy, while heterozygous individuals have antigenic protein C levels less than 60% of normal and present with recurrent venous thrombosis. Acquired deficiencies usually occur in conditions that interfere with hepatic synthetic functions, as these factors are produced in the liver. The onset of episodes of thrombosis, especially venous thrombotic events, in patients with heterozygous deficiency usually begins in their late teens and early twenties. Even then, thrombotic events are often precipitated by another factor, such as trauma, surgery or childbirth. The only established treatment for patients with thrombotic events is heparin therapy followed by lifelong warfarin therapy. Not all patients with these deficiencies will experience episodes of thrombosis, and low levels of either factor by itself in an asymptomatic patient are not an indication for anticoagulation. In a large population of blood donors, 0.3% have been found to have low protein C levels without any overt clinical thrombotic episodes [9].
Although the majority of patients with protein C and protein S deficiencies have venous thrombosis, noted in as many as 4–5% of young patients with venous thrombotic disorders, instances of arterial thromboses have been reported in these deficiency states, especially in young patients [5]. However, the exact incidence of protein C and/or protein S deficiencies in patients with peripheral arterial insufficiency has not been established. Furthermore, given the lack of adequate studies to define the natural history and arteriographic findings of these patients, the treatment has not been well delineated. The presence of this hypercoagulability may influence clinical management. In addition to younger patients, other patients who present with peripheral arterial insufficiency without evidence of atherosclerosis and other risk factors might benefit from hypercoagulability testing. Patients with protein C and/or protein S deficiencies, for whom bypass surgery is an option for critical limb ischaemia, should be treated with full anticoagulation after operation. If there is no contraindication, anticoagulation is continued indefinitely.
We report two cases of patients who presented with peripheral arterial insufficiency and protein C deficiency. One patient was managed with bypass surgery for focal gangrene followed by full anticoagulation. The other patient was managed with full anticoagulation. The arteriographic characteristics of peripheral arterial insufficiency associated with protein C deficiency have not been described. These two cases showed characteristic arteriographic findings: long segment thrombotic occlusion of a main peripheral artery without evidence of atherosclerosis in the aorta and other major arterial vessels. Patients who present with peripheral arterial insufficiency demonstrating thrombotic occlusion of a main peripheral artery without atherosclerosis and other risk factors should be evaluated for hypercoagulable states. Once the diagnosis of protein C and/or protein S deficiency is made, patients should be treated with full anticoagulation. The natural history, arteriographic findings and therapeutic policy, including bypass surgery and thrombolytic therapy, for these patients may require further evaluation by a clinical study.
Received for publication November 28, 2001.
Revision received March 21, 2002.
Accepted for publication June 6, 2002.
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References
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Abstract
Introduction
