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Abstract

Peripheral artery disease (PAD) has been associated with severe morbidity and mortality worldwide, affecting the quality of life for millions of patients. Acute thrombosis has been identified as a major complication of PAD, with proper management including both open as well as endovascular techniques. Thrombolysis has emerged as a reasonable option in the last decades to treat such patients although data produced by randomized trials have been limited. This review aims to present major aspects of thrombolysis in PAD regarding its indications and contraindications, technique tips as well as to review literature data in order to produce useful conclusions for everyday clinical practice.

Keywords

thrombolysis peripheral artery disease review

Introduction

Lower extremity peripheral artery disease (PAD) is a manifestation of systemic atherosclerotic disease, which affects millions of patients and conveys a significant health burden globally [Patel et al. 2015]. Although PAD can be asymptomatic and subclinical, it is associated with a reduction in functional capacity and quality of life when symptomatic and, in its most severe form, is a major cause of limb amputation [Issa et al. 2010]. Thrombosis is highly prevalent in patients with recent symptoms (< 6 months) of claudication or limb ischemia due to occluded culprit lower extremity vessels [Shammas et al. 2012]. Treatment of these thrombotic occlusions is challenging, with thrombolysis being one of the main options. Thrombolysis involves the use of a thrombolytic agent to break down the fibrin contained within a thrombus. Although it has been used as a treatment for acute arterial and graft occlusions for over 30 years, until recently there were no randomized trials to support its use.

Decision making for acute arterial ischemia

The therapeutic options in the management of lower limbs acute ischemia are as follows: (1) classic open repair; (2) percutaneous endovascular repair; and (3) thrombolysis. Peripheral arterial thrombolysis aims for the rapid restoration of blood flow within the ischemic limb as well as the illustration of underlying lesions. It is proven that an immediate release of thrombolytic agents through an endarterial catheter directly into the thrombosed area is much more efficient compared to systematic thrombolysis and it is associated with fewer bleeding complications [Kessel et al. 2004]. Percutaneous catheter-directed thrombolysis is a procedure during which a resolution of the thrombus is achieved percutaneously using special endovascular equipment (sheath, catheter, wires etc.). In this case, thrombolysis is achieved via pharmaceutical agents or in combination with pharmachomechanical means [Richards et al. 2003].

When approaching a patient with acute lower limb ischemia in the Emergency Department, obtaining a detailed medical history is of great significance. Important information includes any history of atrial fibrillation, the status of the contralateral limb, the presence of intermittent claudication as well as a history of past revascularization procedure. Regarding differential diagnosis and possible diagnostic traps, shock, acute compressive neuropathy and phlegmasia cerulea dolens are included [Acosta and Kuoppala, 2015].

The following tests are recommended as preoperative imaging methods: duplex ultrasound, digital angiography that is the golden standard, computed tomography angiography (CTA), and magnetic resonance angiography under certain circumstances. For example, in a case with a popliteal artery aneurysm, coloured Duplex ultrasound or CTA are preferred. Preoperative laboratory tests should include: blood count, coagulation factors measurement as well as renal function tests and blood gases. Finally, a cardiologic evaluation should precede this, mainly to detect an arrhythmia or a silent myocardial infarction, while thrombophilia testing should be under consideration [Morrison, 2006; Palfreyman et al. 2000].

Indications and contraindications for thrombolysis

Conditions that could cause arterial obstruction and have the indication for thrombolysis are the following [Working Party on Thrombolysis in the Management of Limb Ischemia, 2003]:

Acute arterial embolism.

Acute arterial thrombosis.

Underlying stenosis.

Aneurysm presenting with acute thrombosis of the run off vessels.

Acute arterial bypass obstruction.

Trauma (cases of acute arterial thrombosis or dissection; only when bleeding risk of concomitant injuries is low and the vitablity of the limb is at risk).

Dissection.

Thrombolysis during endovascular proce-dures.

Dialysis grafts presenting with acute thrombosis.

Intraoperative thrombolysis.

Indications for thrombolysis include Rutherford class I and IIa acute ischemia as well as class IIb under circumstances (Table 1). One must underline that thrombolysis is not indicated in Rutherford Ischemia class III, which is an indication for primary amputation. Finally, thrombolysis of peripheral arteries is never indicated in patients with intermittent claudication only [Working Party on Thrombolysis in the Management of Limb Ischemia, 2003].

Table 1.

Stages of acute limb ischemia [Rutherford et al. 1997].

Stage	Description	Findings	Arterial Doppler signal
I	Limb viable, not immediately threatened	No sensory loss; no muscle weakness	Audible
IIa	Limb marginally threatened, salvageable if promptly treated	Minimal (toes) or no sensory loss; no muscle weakness	Often audible
IIb	Immediately threatened, salvageable with immediate revascularization	Sensory loss: more than toes, associated with pain at rest; mild or moderate muscle weakness	Usually audible
III	Limb irreversibly damaged, major tissue loss or permanent nerve damage inevitable	Profound sensory loss, anaesthetic; profound muscle weakness, paralysis (rigor)	Inaudible

Contraindications for thrombolysis are classified into absolute and relative [Working Party on Thrombolysis in the Management of Limb Ischemia, 2003; Karnabatidis et al. 2011]:

Absolute:

Stroke or TIA within the last 2 months.

Coagulation disorders (thrombopenia, von Willebrand disease).

Recent gastrointestinal bleeding (<10 days).

Neurosurgery procedure within the last 3 months.

Craniocerebral injury within the last 3 months.

Relative:

Cardiopulmonary resuscitation within the last 10 days.

Surgical procedure or trauma within the last 10 days.

Uncontrolled hypertension.

Highly calcified artery, noncompressible.

Intracranial malignancy.

Recent ophthalmologic procedure.

Minor contraindications:

Liver failure combined with coagulation disorder.

Bacterial endocarditis.

Pregnancy.

Diabetic hemorrhagic retinopathy.

Thrombolytic agents

Common thrombolytic agents include first generation agents, such as streptokinase and urokinase, second generation agents, such as tissue plasminogen activator (tPA) and pro-urokinase, and third generation agents, including reteplase, tenecteplase and Staphylokinase. Thrombolytic agents utilized in the treatment of peripheral arteries disease include streptokinase and urokinase as well as, currently, alteplase [Gabrielli et al. 2015]. However, recent guidelines recommend the use of recombinant tissue plasminogen activator (rtPA) or urokinase rather than the use of streptokinase [Alonso-Coello et al. 2012] (Table 2).

Table 2.

Guidelines and Recommendations regarding thrombolysis for PAD.

American Guidelines on the management of PAD [Hirsch et al. 2006]

• Class I: Catheter-based thrombolysis is an effective and beneficial therapy and is indicated for patients with acute limb ischemia (Rutherford categories I and IIa) of <14 days’ duration. (Level of Evidence: A)

• Class IIa: Mechanical thrombectomy devices can be used as adjunctive therapy for acute limb ischemia due to peripheral arterial occlusion. (Level of Evidence: B)

• Class IIb: Catheter-based thrombolysis or thrombectomy may be considered for patients with acute limb ischemia (Rutherford category IIb) of >14 days’ duration. (Level of Evidence: B)

Further recommendations [Working Party on Thrombolysis in the Management of Limb Ischemia, 2003; Alonso-Coello et al. 2012]

• Patients with graft thrombosis <14 days old should not undergo thrombolysis postoperatively.

• Thrombosis of older grafts with a thrombosis’ duration <14 days should be treated with thrombolysis. Typical embolic events of the lower limbs are usually treated surgically.

• An arterial embolism above the level of the inguinal ligament should be treated surgically.

• If the thrombus has been fragmented and several arterial branches have been occluded, thrombolysis is the therapy of choice.

• Intraoperative intra-arterial thrombolysis is recommended in a case of small distal arteries obstruction (e.g. obstruction of run-off vessels in a thrombosed popliteal artery aneurysm).

• Thrombolysis is not recommended in cases of intermittent claudication.

• In a case of popliteal artery aneurysm thrombosis, thrombolysis is indicated only for revascularization of run-off vessels.

• The catheter should be positioned always within the obstructed vessels. There is no clear indication for thrombolysis in cases with trash foot.

• The use of rtPA or urokinase is recommended rather than the use of streptokinase.

A tPA is derived from the vascular endothelium and is artificially produced using DNA technology, as rtPA. The mechanism of action is the direct activation of plasminogen. Infused intravenously, alteplase remains relatively inactive within the circulation. When connected with the fibrinoid of the thrombus however, it is activated, causing the transformation of plasminogen into plasmin and the subsequent degradation of the thrombus’ fibrinoid. Its half-life is 4–7 min, and the recommended dose is 0.05 mg/kg/hr [Kühn et al. 2011]. According to a recent systematic review on fibrinolytic agents for PAD, there is some evidence to suggest that intra-arterial rtPA is more effective than intra-arterial streptokinase or intravenous rtPA in improving vessel patency in patients with acute arterial occlusion. There was no evidence that rtPA was more effective than urokinase for patients with peripheral arterial occlusion and some evidence that initial lysis may be more rapid with rtPA, depending on the regime. Incidences of haemorrhagic complications were not statistically significantly greater with rtPA than with other regimes. However, all of the findings come from small studies and a general paucity of results means that it is not possible to draw clear conclusions [Robertson et al. 2013].

Regarding the type of infusion, there has been a certain debate in literature. Several studies have evaluated the efficacy and safety of various techniques including intra-arterial delivery and intravenous administration. In a recent systematic review [Kessel et al. 2004], it was found that higher doses and forced infusion achieved vessel patency in less time compared to lower doses, although the former were associated with higher risk of bleeding and no increase in patency rates or improvement in limb salvage at 30 days. Therefore, it seems that the benefit is greater when the agent is delivered into the thrombus, thus reducing the required dose of the drug and avoiding the systematic complications. However, there are some recent cohort studies [Lukasiewicz et al. 2016] confirming the effectiveness and safety of accelerated catheter-directed thrombolysis for acute limb ischemia. Finally, some authors [Allie et al. 2004] have also combined the continuous infusion of a thrombolytic agent with the administration of adjunctive agents such as glycoprotein IIb/IIIa inhibitors, yielding promising results, although these remain still inconclusive.

Principles of the procedure [Kessel et al. 2004; Acosta and Kuoppala, 2015; Karnabatidis et al. 2011; Robertson et al. 2013]

(1) Vascular access:

Usually, the contralateral common femoral artery is punctured and through a crossover catheterization, the catheter is promoted to the level of the thrombosis.

Rarely, the ipsilateral common femoral or popliteal artery could be punctured.

An ultrasound device could offer a great help during vessel puncture.

The quality of vessels, the patency as well as body mass index play a very important role in decision making.

Avoid sites distally from the lesion.

Avoid sites where bleeding is associated with high morbidity, such as axillary artery or translumbar approach.

When the lesion is located distally to the superficial femoral artery (SFA), a promixal ipsilateral and anterograde puncture is performed.

When the lesion is located proximally to the SFA or within the SFA, contralateral puncture of the common femoral artery and crossover approach are performed.

(2) Catheterization process:

After fixation of the sheath, a high-quality angiography is performed, in order to visualize the extent and the type of the lesion.

Outflow and run-off vessels.

Inflow.

(3) Wire and catheter promotion:

Try to promote the wire through the lesion.

Most recent lesions are easier to overcome.

A positive test is a prognostic factor for a successful thrombolysis.

If the promotion of the wire is not successful, then a catheter is positioned just proximally of the thrombus.

If the catheter promotion through the thrombus is not feasible, one should avoid side branches between the tip of the catheter and the lesion.

(4) Infusion of thrombolytic agent:

(i) Bolus infusion through a catheter within the thrombus, followed by a continuous infusion of a low dosage of thrombolytic agent through a pump. It does not show any difficulty and it is the most effective method.

Begin with tPA (dose: 0.5–1 mg/h)

(ii) 25–50 cc/hour of a 10 mg/500cc N/S solution.

(iii) Reference values of fibrinogen, activated partial thromboplastin time (aPTT) and fibrin degradation product (FDP).

(iv) Repeat every 12 h and every 24 h thereafter.

(v) Expected: fall of fibrinogen, rise of FDP levels, prolonged aPTT by 50% (active thrombolysis).

(vi) There is no specific value suggesting a high bleeding risk.

Fibrinogen <150: 4 times higher bleeding risk.

FDP >400: 2.5 times higher bleeding risk.

(vii) If there is no progress in recanalization of the lesion, dosage could be increased by 1 mg/h.

The concomitant infusion of heparin (200–500 units/h; target aPTT 1.25-1.5 times the baseline) is necessary.

(5) Post-thrombolysis actions:

Transfer of the patient into an intensive care unit.

Angiography every 10–12 h.

Dose titration and potential correction of catheter’s position.

Check the puncture sites, check for bleeding, Ht and Hb measurement.

Thrombolysis duration: When the angiographic result is optimal, discontinuation.

Usually 12–48 h, maximum 48–72 h.

(6) Overall risks and benefits:

Risks of the procedure:

Bleeding.

Allergic reactions.

Regarding the sheath-catheter (dissection, vessel injury).

Embolic.

Limitations: Distal embolism, fluid overloading due to continuous rinsing and finally hemolysis, hemoglobinuria

Finally, advantages of this method include:

Lower-risk procedure.

Classic embolectomy destroys arterial endothelium.

Thrombolysis reopens small arteries although this is not feasible with a classic method of revascularization.

It improves inflow and outflow for a subsequent open or endovascular revascularization procedure.

It reduces amputation risk and improves the level of amputation.

Major trials

There are three main multicentre randomized trials comparing thrombolysis with surgical repair to date:

The Rochester Study [Ouriel et al. 1994]: Randomization of 114 patients with acute limb-threatening ischemia. A total of 57 patients underwent thrombolysis with urokinase and 57 underwent an emergency vascular surgery procedure. Amputation-free survival was calculated after 1 year (75% and 52%, respectively). The difference was statistically significant, although there was a higher death rate in the surgical group. This could be attributed to a higher degree of ischemia and a worse preoperative management in the surgical group. Finally, intra-arterial thrombolytic therapy was associated with a reduction in the incidence of in-hospital cardiopulmonary complications and a corresponding increase in patient survival rates.

The STILE trial (Surgery versus Thrombolysis for Ischemia of the Lower Extremity trial) [Weaver et al. 1994]: Overall, 393 patients were randomized (Group A: surgical revascularization, Group B: thrombolysis with rtPA or urokinase). The amputation rate was evaluated in association with the time of the ischemic event (two groups: <14 days ago, and >14 days ago). In cases with an event <14 days ago, patients who underwent thrombolysis showed better results at 6 months, with a much lower amputation rate (11% versus 30%) and a shorter hospital stay. In cases with an event >14 days ago, patients who underwent surgical revascularization showed better results regarding amputation rates (3% versus 12%). Finally, there was no difference between tPA and urokinase regarding efficacy. Overall, the authors concluded that surgical revascularization for lower extremity native artery occlusions is more effective and durable than thrombolysis. Thrombolysis used initially provided a reduction in the surgical procedure for a majority of patients; however, the long-term outcome is inferior, particularly for patients who have a femoro-popliteal occlusion, diabetes, or critical ischemia.

The TOPAS trial (Thrombolysis OR Peripheral Arterial Surgery trial) [Ouriel et al. 1998]: Overall, 544 patients were evaluated. Recombinant urokinase administration was compared to primary surgery in patients with ischemia <14 days ago, and arterial or bypass obstruction. At 6 months, there was no difference (71.8% versus 74.8%) regarding amputation rate. The majority of patients undergoing amputation belonged to the surgical group (94.2%). Mean duration of hospital stay was 10 days in both groups. In the thrombolysis group, patients with thrombosed grafts showed better results regarding thrombus resolution and revascularization as well as less major bleeding events, compared to patients with arterial thrombosis.

Due to some controversial results of the aforementioned trials, a recent systematic review [Berridge et al. 2013] concluded that universal initial treatment with either surgery or thrombolysis cannot be advocated on the available evidence. There is no overall difference in limb salvage or death at 1 year between initial surgery and initial thrombolysis. Thrombolysis may be associated with a higher risk of ongoing limb ischaemia and haemorrhagic complications including stroke. The higher risk of complications must be balanced against risks of surgery in each person. Prognostic factors for long-term outcomes have been identified by several authors. Patients with ischemic heart disease and foot ulcers are at higher long-term risk for both amputation and death [Kuoppala et al. 2008]. A lesser degree of lysis and motor deficit have been associated with higher amputation rates. The presence of such negative prognostic factors may help clinicians to deny further invasive vascular treatment. Furthermore, renal insufficiency, cerebrovascular disease, and acute lower limb ischemia have been also associated with increased mortality [Kuoppala et al. 2008].

Finally, research data have emerged advocating the combined use of contrast-enhanced ultrasound (CEUS) and thrombolysis in the treatment of peripheral arterial thrombosis. In an experimental study by Ebben and colleagues [Ebben et al. 2015], the addition of CEUS accelerated the thrombolytic effect of low-dose intra-arterial thrombolysis in peripheral arterial occlusions. The contrast agent consists of microsized gas-filled bubbles that collapse when exposed to ultrasound, causing destabilization of the clot and making the clot surface more susceptible to fibrinolytics [Acconcia et al. 2014]. A recent Dutch randomized trial [Schrijver et al. 2015] has also shown that thrombolysis time is significantly reduced by ultrasound-accelerated thrombolysis as compared with standard thrombolysis in patients with recently thrombosed infrainguinal native arteries or bypass grafts.

Recommendations

The latest American guidelines on management of PAD [Hirsch et al. 2006] recommend catheter-based thrombolysis in patients with acute limb ischemia of <2 weeks, although this therapeutic strategy could be considered even in cases of older presentation (Table 2). However, one should carefully select the patients who are eligible for thrombolysis, even after the 2 weeks interval, in order to have optimal results and lower risk for complications. Finally, a major consensus, published in 2003 [Working Party on Thrombolysis in the Management of Limb Ischemia, 2003], concluded that thrombolysis is the therapy of choice in cases with fragmentation of thrombus and occlusion of arterial branches. Especially for treating run-off vessels, this technique could offer revascularization even in small distal arteries, although there is still no clear indication for specific cases (for example trash foot) (Table 2).

Conclusion

Current data indicate that thrombolysis is an effective and safe first-line treatment in cases presenting with acute limb ischemia, although long-term outcomes are limited. The selection of eligible patients as well as proper infusion technique remain essential. However, proper rate of infusion as well as novel adjunctive accelerators need to be further evaluated.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

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Thrombolysis in peripheral artery disease

Abstract

Keywords

Introduction

Decision making for acute arterial ischemia

Indications and contraindications for thrombolysis

Thrombolytic agents

Principles of the procedure [Kessel et al. 2004; Acosta and Kuoppala, 2015; Karnabatidis et al. 2011; Robertson et al. 2013]

Major trials

Recommendations

Conclusion

Footnotes

Funding

Conflict of interest statement

References