British Journal of Radiology (2005) 78, 601-605
© 2005 British Institute of Radiology
doi: 10.1259/bjr/65615343
Protein C and/or S deficiency presenting as peripheral arterial insufficiency
Y P Cho, MD1,
T-W Kwon, MD2,
J-H Ahn, MD3,
G H Kang, MD4,
M S Han, MD1,
Y H Kim, MD1,
J H Kwak, MD1 and
S G Lee, MD2
Departments of 1 Surgery, 3 Diagnostic Radiology and 4 Diagnostic Pathology, University of Ulsan Medical College, Gangneung Asan Hospital, 415 Bangdong-ri, Sacheon-myeon, Gangneung, Gangwon-do, 210-711 and 2 Department of Surgery, University of Ulsan Medical College, Seoul Asan Hospital, 388-1 Poongnap-dong, Songpa-gu, Seoul, Republic of Korea
 |
Abstract
|
|---|
Although protein C and/or S deficiency has frequently been associated with venous thromboembolic events, instances of arterial thromboses have been reported. However, the exact incidence of protein C and/or S deficiency in patients with peripheral arterial insufficiency has not been established. Furthermore, given the lack of adequate studies to define the natural history and angiographic findings of these patients, the treatment has not been well delineated. Therefore, we conducted a prospective study to investigate the prevalence, characteristic angiographic findings and optimal treatments in patients with peripheral arterial insufficiency associated with protein C and/or S deficiency. Between September 2000 and August 2004, 133 patients who presented with peripheral arterial insufficiency underwent hypercoagulability tests before the initiation of any treatments. Of these, 11 patients (8.3%) with protein C and/or S deficiency were included in this study. There were nine males and two females. The ages ranged from 38 years to 72 years (mean 57 years). All patients showed characteristic angiographic findings: long segment thrombotic occlusion of a main peripheral artery without evidence of atherosclerosis or with mild atherosclerotic changes in the aorta and other major arterial trees. Surgical or endovascular procedures were performed in nine patients: bypass graft in four, thrombectomy in four and catheter-directed thrombolysis in one. Conservative treatment with full anticoagulation was performed in two patients. All patients received pre- and post-operative anticoagulation. Except for one amputated case, clinical and vascular laboratory improvements were achieved in 10 patients. Mean follow-up period was 21 months (range 4–45 months). However, one patient, in whom re-vascularization surgery was performed successfully, discontinued warfarin therapy himself at 10 months after surgery, graft occlusion and limb loss occurred at 30 months after surgery. This initial experience suggests that protein C and/or S deficiency may be an independent risk factor for peripheral arterial insufficiency. Patients who present with peripheral arterial insufficiency and protein C and/or S deficiency demonstrate characteristic angiographic findings. Once the diagnosis of protein C and/or S deficiency is made, patients should be treated with life-long anticoagulation.
|
Introduction
|
|---|
Protein C is a precursor of a vitamin K-dependent serine protease and is activated by thrombin in the presence of an endothelial cofactor, thrombomodulin and endothelial cell protein C receptor. Activated protein C (protein Ca) proteolytically degrades the procoagulant cofactors Va and VIIIa in the presence of protein S. Therefore, it serves as an anticoagulant protein [1–11]. Although several reports have suggested a relationship between protein C and/or S deficiency and peripheral arterial insufficiency (PAI), it is still uncertain.
The purpose of this study was to investigate the prevalence, characteristic angiographic findings and optimal treatments in patients with PAI associated with protein C and/or S deficiency.
|
Materials and methods
|
|---|
From September 2000 to August 2004, angiograms (transfemoral conventional angiogram or multidetector CT; GE CT LightSpeed Ultra 16, GE, Milwaukee, WI) and hypercoagulability tests were performed in 133 patients with proven PAI. The diagnosis of PAI was confirmed by characteristic clinical, segmental leg pressure examination, and/or colour Doppler ultrasound. Of these, 11 patients (8.3%) with the diagnosis of PAI associated with protein C and/or S deficiency were included in this study. Risk factors included smoking (7 cases; 63.6%), hypertension (1 case; 9.1%), diabetes mellitus (1 case; 9.1%), and hyperlipidaemia (1 case; 9.1%). Other hypercoagulability abnormalities were antithrombin III deficiency (1 case; 9.1%) and hyperhomocysteinaemia (1 case; 9.1%). Neither collagen disease nor cardiac disease had ever been diagnosed in all patients.
Hypercoagulability tests were carried out before the initiation of any treatments. Antigenic protein C and S levels were measured using human protein C/S "NL" NANORIDTM radial immunodiffusion kit (the Binding Site Ltd, Birmingham, UK), and the diagnosis of protein C and S deficiencies was confirmed if antigenic protein C and S levels were less than 60% of normal. We did not perform family studies for protein C and/or S deficiency, because 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. Informed consent was obtained in all patients after the risks and benefits of treatment were fully explained. We analysed the clinical characteristics, treatment modalities, and the outcomes in these patients.
|
Results
|
|---|
The 11 consecutive patients with PAI and protein C and/or S deficiency were 9 males and 2 females, aged 38–72 years (mean 57 years). Clinical characteristics are summarized in Table 1
. Rest pain was the most common clinical manifestation and noted in 9 out of 11 patients (81.8%). The time intervals from the onset of symptoms to the initiation of treatment ranged from 1 day to 12 months with an average duration of 2.4 months. Antigenic protein C and/or S levels obtained prior to systemic anticoagulation therapy were less than 60% of normal in all patients. Angiograms (eight transfemoral conventional angiograms and three multidetector CT) confirmed the level of the occlusion: aorto-iliac occlusion in two patients, ilio-femoral in four, femoral in three, and popliteal in two. All patients showed characteristic angiographic findings: long segment thrombotic occlusion of a main peripheral artery without evidence of atherosclerosis or with mild atherosclerotic changes in the aorta and other major arterial trees (Figures 1–3).
View this table:
[in this window]
[in a new window]
|
Table 1. Details of patients with peripheral arterial insufficiency associated with protein C and/or S deficiency
|
|
View larger version (174K):
[in this window]
[in a new window]
|
Figure 1. In case 1, transfemoral angiogram showed long segment thrombotic occlusion of the right external iliac, common, and superficial femoral arteries without evidence of atherosclerosis in the aorta and other major arterial trees.
|
|
View larger version (78K):
[in this window]
[in a new window]
|
Figure 2. In case 7, (a) segmental leg pressure examination showed absence of Doppler waveform at both calf and ankle levels. (b) Transfemoral angiogram revealed complete thrombotic occlusion of the right common iliac artery, left superficial and deep femoral arteries. Note that the abdominal aorta showed normal anatomy and luminal patency without evidence of atherosclerosis. (c) Histopathologically, the femoral artery was almost totally occluded by the organized thrombi (haematoxylin and eosin stain, x 40). The arterial wall showed no pathological abnormalities.
|
|
View larger version (89K):
[in this window]
[in a new window]
|
Figure 3. Multidetector CT in case 11. (a) Pre-operative multidetector CT showed partial eccentric thrombus involving infrarenal abdominal aorta (black arrows) and complete thrombotic occlusion of the right proximal external iliac artery. (b) Post-operative multidetector CT showed good patency of the right external iliac artery.
|
|
After the angiograms were taken, surgical or endovascular procedures were performed in nine patients: bypass graft in four, thrombectomy in four and catheter-directed thrombolysis in one. Conservative treatment with full anticoagulation was performed in two patients: one with superficial femoral artery occlusion complained of mild claudication (case 2) and the other with ilio-femoral artery occlusion complained of severe ischaemic rest pain (case 7). In case 7, segmental leg pressure examination showed absence of Doppler waveform at both calf and ankle levels (Figure 2a
) and angiogram revealed complete obstruction of the right common iliac artery without sparing of the arteries of the foot (Figure 2b). Distal arterial reconstruction was not possible, and conservative treatment with full anticoagulation and analgesics was performed. However, the patient continued experiencing persistent ischaemic rest pain and detectable loss of sensation below the knee. 7 days later, an above-the-knee-amputation was done. Histopathological findings revealed that the femoral artery was almost totally occluded by the organized thrombi. The arterial wall showed no pathological abnormalities (Figure 2c). All patients were given pre- and post-operative anticoagulants with a regimen of heparin and later, orally administered life-long warfarin, adjusted to maintain a prothrombin time of 2.0 and followed up both clinically and by segmental leg pressure examination at the time of hospital discharge, every 3 months for the first 6 months and every 6 months thereafter. Except for one patient with primary amputation, clinical and vascular laboratory improvements were achieved in 10 patients.
Mean follow-up period was 21 months (range 4–45 months), and there was no operative or procedure related mortality or morbidity in any patient. However, one patient, in whom common iliac artery-deep femoral artery-distal posterior tibial artery bypass was performed successfully, discontinued warfarin therapy himself at 10 months after surgery, graft occlusion and limb loss occurred at 30 months after surgery (case 1).
|
Discussion
|
|---|
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. Among the numerous conditions that can lead to a hypercoagulable state, proteins C and S deficiencies have been frequently described [1–11]. Proteins C and S are two of the vitamin K-dependent proteins. Protein Ca inactivates factors Va and VIIIa. Protein C is activated to protein Ca 20 000 times faster than by thrombin alone through the interaction of thrombomodulin and thrombin on the endothelial cell surface [12]. In addition, protein C proteolytically inactivates the inhibitor to tissue plasminogen activator, 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. Proteins C and S deficiencies may be seen in both congenital and acquired forms. They are inherited in an autosomal dominant manner. In congenital conditions, homozygous deficiency of protein C is associated with life-threatening thrombotic disease occurring in the neonatal period, whereas individuals with heterozygous deficiencies have antigenic protein C levels less than 60% of normal and suffer an increased risk of venous thrombosis later in life [3–11, 13, 14]. Acquired deficiencies are usually associated with 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 is known to begin in the late teens and 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 life-long 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 [15].
It is well known that protein C and/or S deficiency causes recurrent venous thrombotic events [1–11]. Concerning the relationship between the protein C and/or S deficiency and arterial occlusion, several reported arterial occlusive patients with protein C and/or S deficiency and a prospective study suggested the involvement of low protein C and/or S levels to myocardial infarction [16–18]. However, the exact incidence of protein C and/or S deficiency in patients with PAI has not been established. Furthermore, given the lack of adequate studies to define the natural history and angiographic findings of these patients, the treatment has not been well delineated.
In our small series, protein C and/or S deficiency is not an uncommon condition in patients with PAI. They showed characteristic angiographic findings: long segment thrombotic occlusion of a main peripheral artery without evidence of atherosclerosis or with mild atherosclerotic changes in the aorta and other major arterial trees. Therefore, patients who presents with PAI demonstrating this characteristic angiographic findings should be evaluated for hypercoagulable states. Once the diagnosis of protein C and/or S deficiency is made, patients should be treated with full anticoagulation. Curi et al [19] reported that patients with serologically proven hypercoagulability have inferior long-term patency, limb salvage, and survival rates after infrainguinal bypass. Therefore, patients with protein C and/or S deficiency 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. During the past several years, catheter-directed thrombolysis and endovascular stents have been used to treat arterial occlusive disease, as an alternative to bypass surgery, in selected cases. In patients undergoing coronary thrombolysis, Gruber et al [20] showed an 11-fold increase in protein Ca during thrombolysis. They concluded that thrombolytic therapy generates at least two potent antithrombotic factors in the circulation, namely the fibrinolytic enzyme, plasmin, and the anticoagulation enzyme, protein Ca. Therefore, we speculate that endogenous protein Ca generated during thrombolysis has more potent antithrombotic effects in patients with PAI caused by protein C and/or S deficiency. Protein Ca may help prevent re-thrombosis during or after thrombolysis. Catheter-directed thrombolysis, if performed soon after the onset of symptoms, may be one of the effective treatment modality in selected patients with PAI and protein C and/or S deficiency.
In summary, this initial experience suggests that protein C and/or S deficiency is not an uncommon condition in patients with PAI and may be an independent risk factor for PAI. Patients who present with PAI demonstrate thrombotic occlusion of a main peripheral artery without atherosclerosis or with mild atherosclerotic changes in the aorta and other major arterial trees should be evaluated for hypercoagulable states. Once the diagnosis of protein C and/or S deficiency is made, patients should be treated with full anticoagulation. The natural history, angiographic findings and therapeutic policy including bypass surgery and thrombolytic therapy, for these patients may require further evaluation by a clinical study.
Received for publication December 1, 2004.
Revision received January 6, 2005.
Accepted for publication January 26, 2005.
|
References
|
|---|
- Eldrup-Jorgensen J, Flanigan DP, Brace L, Sawchuk AP, Mulder SG, Anderson CP, et al. Hypercoagulable states and lower limb ischemia in young adults. J Vasc Surg 1989;9:334–41.[CrossRef][Medline]
- Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, et al. Inherited thrombophilia: Part 1. Thromb Haemost 1996;76:651–62.[Medline]
- Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, et al. Inherited thrombophilia: Part 2. Thromb Haemost 1996;76:824–34.[Medline]
- De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996;87:3531–44.[Free Full Text]
- Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briet E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993;341:134–8.[CrossRef][Medline]
- De Stefano V, Leone G, Mastrangelo S, Tripodi A, Rodeghiero F, Castaman G, et al. Clinical manifestations and management of inherited thrombophilia: retrospective analysis and follow-up after diagnosis of 238 patients with congenital deficiency of antithrombin III, protein C, protein S. Thromb Haemost 1994;72:352–8.[Medline]
- Sakata T, Kario K, Katayama Y, Matsuyama T, Kato H, Miyata T. Studies on congenital protein C deficiency in Japanese: prevalence, genetic analysis, and relevance to the onset of arterial occlusive diseases. Semin Thromb Haemost 2000;26:11–6.[CrossRef][Medline]
- Sakata T, Kario K, Katayama Y, Matsuyama T, Kato H, Miyata T. Analysis of 45 episodes of arterial occlusive disease in Japanese patients with congenital protein C deficiency. Thromb Res 1999;94:69–78.[CrossRef][Medline]
- Clouse LH, Comp PC. The regulation of hemostasis: the protein C system. N Engl J Med 1986;314:1298–304.[Medline]
- Cho YP, Lee DH, Jang HJ, Kim JS, Han MS, Lee SG. Peripheral arterial insufficiency associated with protein C deficiency. Br J Radiol 2002;75:843–6.[Abstract/Free Full Text]
- Cho YP, Jang HJ, Lee DH, J Ahn, Han MS, Kim JS, et al. Deep venous thrombosis associated with protein C and/or S deficiency: management with catheter-directed thrombolysis. Br J Radiol 2003;76:380–4.[Abstract/Free Full Text]
- Hingorani A, Ascher E, Yorkovich W, Mazzariol F, Jacob T, Gunduz Y, et al. Upper extremity deep venous thrombosis: an underrecognized manifestation of a hypercoagulable state. Ann Vasc Surg 2000;14:421–6.[CrossRef][Medline]
- Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, et al. Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1995;73:876–89.[Medline]
- Bovill EG, Bauer KA, Dickerman JD, Callas P, West B. The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 1989;73:712–7.[Abstract/Free Full Text]
- Esmon CT. The regulation of natural anticoagulant pathways. Science 1987;235:1348–52.[Abstract/Free Full Text]
- Kohler J, Kasper J, Wett I, von Reutern GM. Ischemic stroke due to protein C deficiency. Stroke 1990;21:1077–80.[Abstract/Free Full Text]
- De Stefano V, Leone G, Micalizzi P, Teofili L, Falappa PG, Pollari G, et al. Arterial thrombosis as clinical manifestation of congenital protein C deficiency. Ann Hematol 1991;62:180–3.[CrossRef][Medline]
- Kario K, Matsuo T, Tai S, Sakamoto S, Yamada T, Miki T, et al. Congenital protein C deficiency and myocardial infarction: concomitant factor VII hyperactivity may play a role in the onset of arterial thrombosis. Thromb Res 1992;67:95–103.[CrossRef][Medline]
- Curi MA, Skelly CL, Baldwin ZK, Woo DH, Baron JM, Desai TR, et al. Long-term outcome of infrainguinal bypass grafting in patients with serologically proven hypercoagulability. J Vasc Surg 2003;37:301–6.[CrossRef][Medline]
- Gruber A, Pál A, Kiss RG, Sas G, Griffin JH. Generation of activated protein C during thrombolysis. Lancet 1993;342:1275–6.[CrossRef][Medline]
Top
Abstract
Introduction
