British Journal of Radiology (2003) 76, 380-384
© 2003 British Institute of Radiology
doi: 10.1259/bjr/47736122
Deep venous thrombosis associated with protein C and/or S deficiency: management with catheter-directed thrombolysis
Y P Cho, MD
1
H J Jang, MD
1
D H Lee, MD
2
J Ahn, MD
2
M S Han, MD
1
J S Kim, MD
1
Y H Kim, MD
1 and
S G Lee, MD
3
Department of 1 Surgery and 2 Diagnostic Radiology, Gangneung Asan Hospital, 415 Bangdong-ri, Sacheon-myeon, Gangneung and 3 Department of Surgery, Seoul Asan Hospital, 388-1 Poongnap-dong, Songpa-Gu, Seoul, Republic of Korea
Correspondence: Yong Pil Cho, Department of Surgery, University of Ulsan College of Medicine, Gangneung Asan Hospital, 415 Bangdong-ri, Sacheon-myeon, Gangneung-si, Gangwon-do, Republic of Korea, 210-711
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Abstract
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We performed this study to evaluate the efficacy of catheter-directed thrombolysis with urokinase in treating acute symptomatic iliofemoral deep venous thrombosis associated with protein C and/or S deficiency. A total of 42 consecutive patients with deep venous thrombosis were seen between September 2000 and August 2002. Of these, catheter-directed thrombolysis via the popliteal vein was performed in 5 patients (11.9%) with acute iliofemoral deep venous thrombosis associated with protein C and/or S deficiency. Average duration of symptoms was 4.2 days (range, 1–7 days). The average urokinase dose was 2.7 million IU (range, 0.6 million to 7.0 million IU) infused over an average of 33.1 h (range, 16–67 h). Lysis was complete in all five treated cases. Two cases had underlying iliac venous stenoses (>50%) that were treated with angioplasty and stent placement. In one patient in whom recanalization of a right iliac vein occlusion was successful, thrombosis occurred in the treated vein within 3 weeks of intervention despite full anticoagulation therapy, and further intervention was required. There were no complications or clinically detectable pulmonary emboli. The technical and clinical success rates were 100%. This initial experience suggests that catheter-directed thrombolysis for treatment of acute symptomatic iliofemoral deep venous thrombosis associated with protein C and/or S deficiency is safe and effective.
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Introduction
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There are a number of conditions that can lead to a hypercoagulable state. Proteins C and S deficiencies are frequently described as causes of the hypercoagulable states [1–9]. Although instances of arterial thromboses have been reported, proteins C and S deficiencies have frequently been associated with venous thromboembolic events [1–7]. Traditional therapy for iliofemoral deep venous thrombosis (DVT) has been systemic heparin followed by oral warfarin. Despite widespread use of this method, the results have been largely inadequate in terms of rapid resolution of symptoms, recanalization of long-segment venous occlusions, and long-term disability from chronic venous insufficiency [10–13]. Thrombolysis for DVT, if performed soon after the onset of symptoms, has the potential to prevent damage to the deep valves, thus maintaining the integrity and preventing post-thrombotic complications in the future [13–17]. Given the lack of adequate studies to define the natural history and the efficacy of anticoagulation in patients with DVT associated with protein C and/or S deficiency, whether or not catheter-directed thrombolysis is safe and effective in these patients is unclear. The purpose of this study was to evaluate the efficacy of catheter-directed thrombolysis with urokinase in treating acute symptomatic iliofemoral DVT associated with protein C and/or S deficiency.
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Materials and methods
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Patients
A total of 42 consecutive patients with DVT were seen between September 2000 and August 2002. The diagnosis of DVT was confirmed by characteristic clinical, colour Doppler ultrasound and/or conventional venographic findings. Of these, 7 patients (16.7%) were diagnosed with DVT associated with protein C and/or S deficiency. Hypercoagulability studies were carried out before thrombolysis and systemic anticoagulation therapy. 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. In this study, two protein C and/or S deficiency patients did not receive catheter-directed thrombolysis: due to an isolated infrainguinal DVT in one patient and a chronic DVT in the other. Five patients with acute iliofemoral DVT (symptoms of less than 10 days' duration) and protein C and/or S deficiency were treated with catheter-directed thrombolytic therapy and were included in this study (Table 1
). Informed consent was obtained in all patients after the risks and benefits of treatment were fully explained.
Procedure
Of the 42 patients, catheter-directed thrombolysis was performed in 9 patients (21.4%) with symptoms of less than 10 days' duration and a diagnosis of iliofemoral DVT confirmed by colour Doppler ultrasound: 5 with protein C and/or S deficiency and 4 without protein C and/or S deficiency. Local catheter-directed thrombolytic therapy with urokinase was performed under fluoroscopic guidance. Although this drug has been withdrawn from clinical use in the UK and USA, we used urokinase as the thrombolytic agent in this study. With the patient in prone position, venous access was through the ipsilateral popliteal vein under ultrasound guidance. An 8-Fr or 9-Fr vascular sheath (Check-flo; Cook, Bloomington, IN, USA) was placed and direct venography was obtained to estimate the severity and extent of the thrombosis above the popliteal vein. Before the insertion of the infusion catheter for thrombolysis, we aspirated part of the filling defect through a longer, small-bore vascular sheath in order to reduce the duration and the dose of thrombolytics. Following this manoeuvre a 5-Fr multiside-hole infusion catheter (Cook, Bloomington, IN, USA) was inserted through the sheath. Urokinase was reconstituted by using 500 000 IU in 100 ml of 0.9% NaCl and delivered in continuous low dose of 500 IU min-1 to 2000 IU min-1 via thrombolysis catheter. Patients were systemically treated with heparin during the procedure through the side arm of the venous sheath after a loading bolus of 5000 IU. Partial thromboplastin time values were obtained at every 4 h after the start of thrombolytic therapy, and the heparin infusion rate was adjusted to maintain the partial thromboplastin time range with 50 s to 90 s. Follow-up venography was performed within 12 h of the start of thrombolytic therapy. The position of the catheter was changed to facilitate effective thrombolysis. After thrombolysis, further intervention was performed if there was an underlying venous stenosis of greater than 50%. Intervention consisted of angioplasty and stent placement. The venous stenoses were predilated with an 8- or 10-mm diameter balloon (Ultra-Thin Diamond; Boston Scientific Co., Watertown, MA, USA) before stent placement (Wallstent; Boston Scientific Co., Watertown, MA, USA). All stents were placed above the inguinal ligament.
Outcome variables
Lysis was considered complete if there was less than 5% residual luminal (area) narrowing [13–15]. Technical success was defined as complete recanalization of the vein with less than 30% residual luminal (area) narrowing. Clinical success was defined as complete or partial resolution of low extremity pain and oedema. After the procedure, patients were anticoagulanted with a regimen of heparin initially, followed by orally administered warfarin.
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Results
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Overall, there were technical and clinical success rates of 100% for treated limbs. The average duration of therapy was 33.1 h (range, 16–67 h), and the average total urokinase dose was 2.7 million IU (range, 0.6 million to 7.0 million IU). Lysis was complete in all patients. Two cases with underlying venous stenoses (>50%) were treated with angioplasty and stent placement (Figure 1). The mean follow-up was 10.6 months (range, 5–23 months) and there were no complications or clinically detectable pulmonary emboli.
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Figure 1. Venograms of complete thrombolysis with underlying focal stenosis treated with an endoluminal stent in case 2 with acute left leg swelling and pain for 5 days. Doppler ultrasound revealed acute DVT extending from the calf vein into the common iliac vein. (a) In the prone position, ascending venogram demonstrated an acute thrombus extending into the common iliac vein. (b) After 25 h of thrombolytic therapy, flow was restored within the common iliac vein; however, there was a focal stenosis in the common iliac vein (arrow). (c) The common iliac vein was treated with angioplasty and stent placement. (d) Final subtraction venogram showed complete resolution of iliac vein flow and no residual filling defect.
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There was one heparin-induced thrombocytopenia in which the patient's platelet count dropped from 314 000 µl-1 to 12 000 µl-1 (case 1). All heparin infusions and flushes were immediately stopped, and anticoagulation with low-molecular-weight heparin (dalteparin sodium, Fragmin®; Pharmacia, Stockholm, Sweden) followed by warfarin was instituted. The patient's platelet count steadily increased over the next 5 days, returning to normal level, consistent with a diagnosis of heparin-induced thrombocytopenia. The leg oedema and pain were significantly reduced the day after thrombolytic therapy, and were absent upon discharge and at 23 months follow-up. In another patient in whom recanalization of a right iliac vein occlusion was successful, thrombosis occurred in the treated vein within 3 weeks of intervention despite full anticoagulation therapy being given (case 4). The patient was treated with repeated catheter-directed thrombolysis and anticoagulation with heparin followed by orally administered warfarin. 1 month after the repeated thrombolytic therapy, follow-up colour Doppler ultrasound showed continued patency of the treated vein and at 5 months follow-up, the patient remained asymptomatic.
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Discussion
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Conventional treatment of iliofemoral DVT has typically consisted of systemic heparin therapy followed by anticoagulation with oral warfarin. However, with anticoagulation, eventual recanalization of the occluded vessel depends solely on the effectiveness of the patient's own fibrinolytic system. Anticoagulation does not protect the patient from the manifestations of post-thrombotic syndrome, which can appear months to years after the acute episode of DVT [12–17]. Long-term studies in patients with iliofemoral DVT treated with anticoagulation alone have demonstrated that muscle pump function and valvular competency are severely compromised in approximately 95% of patients at 5-year follow-up despite improvement in venous outflow [18]. The therapeutic goals for treating the patient with acute DVT include prevention of pulmonary embolism, restoration of unobstructed blood flow through the thrombosed segment, prevention of recurrent thrombosis, and preservation of venous valve function [13]. Considering that success in the achievement of these clinical goals will minimize the morbidity and mortality associated with DVT, catheter-directed thrombolysis is a potentially attractive form of therapy: (1) it delivers high concentrations of thrombolytic agents directly into the thrombus while minimizing the potential for a systemic fibrinolytic effect; (2) it provides the opportunity for the prompt restoration of venous patency and preservation of venous valve function. This therapy can potentially help prevent long-term sequelae of DVT with acceptable complication rates.
In our small series, lysis was complete in all five treated cases without complications or clinically detectable pulmonary emboli. Two cases had underlying iliac venous stenoses that were treated with angioplasty and stent placement. During catheter-directed thrombolysis, major bleeding complications are primarily related to the catheter insertion site [13]. Cautious needle access under the ultrasound guidance is mandatory to avoid inadvertent puncture of adjacent vessels such as the popliteal artery. A theoretical consideration with catheter-directed thrombolysis is dislodgement of significant thrombotic material, leading to a pulmonary embolus. There is a relatively high incidence of asymptomatic pulmonary emboli in iliac venous thrombosis, as shown by scintigraphy [19]. Although the true prevalence of pulmonary emboli is unknown in our study, there were no clinically significant cases of pulmonary emboli resulting in increasing dyspnoea or arterial oxygen desaturation. We did not perform scintigraphy or insert caval filters.
The term "hypercoagulable state" is generally used to denote any conditions in which the normal balance between clotting and anticlotting mechanisms becomes altered in such a way that the patient is predisposed to thrombus formation. There are a number of conditions that can lead to a hypercoagulable state. Proteins C and S deficiencies are frequently described as causes of the hypercoagulable states [1–9]. Proteins C and S are two of the vitamin K-dependent proteins. Activated protein C (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 [20]. In addition, protein C proteolytically inactivates the inhibitor to tissue plasminogen activator, thus increasing the natural fibrinolytic activity of plasma. Protein S is a co-factor for protein C. The activity of protein Ca is increased several orders of magnitude by its non-enzymatic co-factor 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 the congenital conditions, those homozygous for protein C deficiency usually die in infancy, while heterozygous have antigenic protein C levels less than 60% of normal and present with recurrent venous thrombosis. Acquired deficiencies are usually associated with conditions that interfere with hepatic synthetic functions, as these factors are produced in the liver. Although all patients in this study were over 40 years of age, 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 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 [21]. Instances of arterial thromboses have been reported, especially in young patients, but the majority of patients with protein C and/or S deficiency have venous thrombosis, noted in as many as 4% and 5% of young patients with venous thrombotic disorders [1–9]. Although anticoagulation with heparin has been the treatment of choice for most patients with DVT, catheter-directed thrombolysis for symptomatic iliofemoral DVT may be safe and effective in selected cases. Given the lack of adequate studies to define the natural history and the efficacy of anticoagulation in patients with DVT associated with protein C and/or S deficiency, whether or not catheter-directed thrombolysis is safe and effective in these patients is unclear. In patients undergoing coronary thrombolysis, Gruber et al showed an 11-fold increase in protein Ca during thrombolysis [22]. 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. Although protein Ca levels were not measured during or after thrombolysis in our study, we speculate that endogenous protein Ca generated during thrombolysis has more potent antithrombotic effects in patients with DVT and protein C and/or S deficiency. Protein Ca may help prevent rethrombosis during or after thrombolysis.
In summary, the presence of this hypercoagulability may influence clinical management. In addition to younger patients, other patients who presented with acute, massive iliofemoral DVT not precipitated by other risk factors might benefit from hypercoagulability testing. If there are no contraindications, patients with DVT associated with this hypercoagulability should be treated with full anticoagulation indefinitely. Also, catheter-directed thrombolysis for the treatment of these patients requires further evaluation with full clinical study and this presentation shows only the initial experience of this therapeutic modality as a safe and effective method for treating acute iliofemoral DVT with protein C and/or S deficiency.
Received for publication October 22, 2002.
Revision received February 11, 2003.
Accepted for publication March 12, 2003.
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Abstract
Introduction
