Percutaneous Mechanical Thrombectomy and Fibrinolytic Therapy for Acute Thrombosis of Lower Extremity Arteries and Grafts

Acute, pathologic arterial and graft clot formation can severely compromise distal perfusion beds of the leg and commonly requires immediate treatment. The decrease in distal blood flow and the resultant tissue hypoxia promote thrombus deposition in the small nutrient vessels. Although a variety of methods can be used for extracting clot from larger arteries, the smaller distal vessels cannot be easily reopened with standard surgical thrombectomy catheters. Attempts to do so can inflict more damage to these conduits, injuring flow surfaces and disrupting smaller arteries, thereby preventing reperfusion. Thus, alternatives to open surgical thrombectomy are essential. Percutaneous mechanical thrombectomy and thrombolytic therapy are procedures that can remove major clot and induce clot lysis, often without additional arterial injury. The safe use of these treatments requires careful patient selection based on a clear understanding of the methods of clot extraction, normal mechanisms of clot formation, and the process of fibrinolysis.

Percutaneous Mechanical Thrombectomy Devices

The purpose of percutaneous mechanical thrombectomy devices is to soften, fragment, and extract occlusive thrombus. They may be used without adjunctive thrombolytic therapy, although many patients require both modalities for effective treatment. The therapies are complementary; the device is capable of reducing or eliminating the thrombus burden as well as modifying the clot to expose more surface area to the lytic agent. There are a variety of technologies to accomplish this. Suction, ultrasound, fluid, and mechanical methods have been developed ( Table 1 ). Suction catheters represent the first generation of these devices and are used to simply evacuate the clot by placing a vacuum at the tip of any large catheter buried within the clot and withdrawing the catheter with the attached thrombus. This procedure is moderately effective for the extraction of short, fresh clot but is generally of little benefit as solo therapy for the treatment of acute ischemia from long or adherent thrombus.

TABLE 1

Commonly Used Percutaneous Mechanical Thrombectomy Devices

Device	Manufacturer	Mechanism of Clot Disruption
Ekosonic Catheter	EKOS	High-frequency ultrasound
Angiojet Thrombectomy System	Medrad	Rheolytic fluid dynamics
Trellis Infusion Catheter	Bacchus Vascular	Direct physical disruption

The currently available ultrasound catheter system uses high-frequency, low-power, pulsed-wave ultrasound to fragment clot and permit greater contact with a thrombolytic agent. This system has been effective in lowering the thrombolytic infusion time to reperfusion of the distal leg from more than 24 hours to less than 16.5 hours.

Several mechanical devices use fluid dynamics to extract significant portions of the thrombus and increase the surface area of the remnant for thrombolytic therapy. To create a rheolytic effect, a backward-directed jet of fluid is used to disrupt the clot. The particles then circulate forward and are aspirated into the catheter to reduce the likelihood of peripheral embolization. After clot extraction has been maximized, many patients receive a shortened course of thrombolytic therapy. The rheolytic effect is associated with some hemolysis, but the extent of hemolysis is usually not severe or limiting.

Catheter systems have also been developed to isolate the treatment segment during the administration of thrombolytic agents to significantly enhance the thrombolytic effect and reduce infusion time and the risk of hemorrhage from a systemic lytic state. In such a system, proximal and distal occlusion balloons are inflated in the artery or graft to be treated. A sinusoidal wire is rotated in the intervening segment to disrupt the clot while lytic agents are being infused. The particulate debris generated by this process is evacuated through the catheter to prevent distal embolization. When used in conjunction with tissue plasminogen activator (tPA), this system has been shown to reduce overall treatment time to less than 3 hours. This is an acceptable time to reperfusion for the treatment of many patients with class I, class IIa, and class IIb acute ischemia. Although the system is effective in reducing treatment times, unfortunately, distal embolization may be problematic and can prolong distal tissue ischemia.

Although percutaneous mechanical thrombectomy devices can expedite the course of treatment of thrombolytic therapy, catheter-directed infusion of lytic agents into fresh clot remains an effective percutaneous means of establishing distal reperfusion.

Mechanisms of Clot Formation and Dissolution

Several factors are capable of initiating thrombus formation, and many of them are poorly characterized. There is a continuous low level of spontaneous intravascular conversion of fibrinogen and plasminogen to active forms. This process is held in check by numerous circulating antithrombins and antiplasmins. The balance between fibrin formation and degradation is altered by tissue injury associated with endothelial cell damage. This causes a rapid increase in factor XII, Hageman factor, which initiates the series of complex enzymatic interactions of the intrinsic pathway of the clotting cascade. The formation of the hemostatic fibrin plug entraps both cellular and humoral factors, including plasminogen.

During thrombus development, Hageman factor also enhances the conversion of soluble plasminogen to plasmin. This process confines thrombus formation to the area of injury but does little to begin clot dissolution. Lysis of the thrombus results from the activation of clot-bound plasminogen. This is initiated by the release of the plasminogen activator from injured endothelial cells in the area of tissue injury during clot formation. Because there is a paucity of plasmin inhibitors within clot, active plasmin can function in a relatively unopposed fashion. Conversion of clot-bound plasminogen, however, is inefficient, and spontaneous clot lysis is slow and rarely complete. Fibrinolytic agents enhance the conversion of plasminogen to plasmin and therefore accelerate clot lysis both locally and systemically.

Fibrinolytic Agents

The goal of fibrinolytic therapy is the acceleration of clot dissolution through the direct or indirect degradation of fibrin, the basic framework of clot. Optimally, this would be limited to the pathologic clot in the immediate vicinity of drug deposition to preserve the body’s ability to deposit and maintain thrombus elsewhere, such as at puncture sites, incisions, and mucosal ulcerations. Several agents have been developed to achieve this result; however, none have demonstrated true selectivity. At this time, all clinically approved fibrinolytic agents cause the degradation of both fibrin and fibrinogen.

Streptokinase, the oldest of the available agents, is a product of Lancefield group C β-hemolytic Streptococcus. It combines with plasminogen to form a streptokinase–plasminogen activator complex. The complex then activates other molecules of plasminogen both within the circulating plasma and within the clot. Efficacy of this agent is limited because human plasma often contains antibodies against it from prior streptococcal infections. Also, the requirement to bind to plasminogen to form an activator complex reduces the available clot-bound plasminogen for activation. Therefore this agent must recruit and cleave circulating plasminogen into plasmin to accelerate clot dissolution. Circulating plasmin attacks not only fibrin strands within a clot but also circulating molecules of fibrinogen. A significant reduction in fibrinogen levels is the hallmark of the systemic lytic state and correlates with the risk of hemorrhagic complications. Because of the immune response to streptokinase, the adverse effect upon circulating fibrinogen levels, and the significant systemic lytic state and hemorrhagic complications associated with the use of this drug, it has generally been replaced by more clot-specific thrombolytic agents for the treatment of acute arterial or graft occlusion.

Urokinase is an endogenous compound that is capable of directly converting plasminogen to plasmin. Although initially isolated from human urine, urokinase is now obtained from cultures of fetal kidney cells. This fibrinolytic agent demonstrates a slightly higher affinity for clot-bound plasminogen than circulating molecules. However, because the administered agent does not have enhanced ability to penetrate thrombus, it also cleaves circulating fibrinogen molecules and therefore has a significant systemic lytic effect.

Recombinant human tPA (rh-tPA) is another of the endogenous plasminogen-converting enzymes derived from cell culture. As with urokinase, rh-tPA directly activates plasminogen without an intermediary complex. It demonstrates greater specificity for clot-bound plasminogen than either streptokinase or urokinase but does not have specific clot-penetrating properties. Therefore, intraarterial administration also induces systemic soluble plasminogen activation. It has a half-life of approximately 5 to 7 minutes.

Reteplase is another form of recombinant tPA. This drug differs from the others discussed here in that it has been modified for a longer half-life of approximately 15 minutes. It also has a lower binding strength to fibrin. This latter characteristic enables the drug to more effectively penetrate into the clot rather than remain bound to clot surface fibrin. In this way the drug can expedite thrombolysis.

Tenecteplase is also a modified form of recombinant tPA. The mechanism of action is the same as that of recombinant tPA, but tenecteplase has been genetically engineered to have a greater fibrin specificity and greater resistance to plasminogen activator inhibitor 1 (PAI-1), yielding a longer half-life of 20 minutes. The greater fibrin specificity can result in a decreased systemic lytic state and fewer hemorrhagic complications during infusion.

Indications for Thrombolytic Therapy

Patient Selection

Thrombolytic therapy should be considered as a treatment option for all patients who have an acute lower extremity thrombosis of less than 14 days’ duration. However, it should only be used to treat significant ischemia after careful patient selection. Acute interruption in lower extremity perfusion can manifest with various levels of ischemia. It is well recognized that the impact of acute arterial or graft occlusion is inversely proportional to the extent of collateral blood flow.

Several degrees of severity of lower extremity ischemia can accompany acute arterial or graft occlusion ( Table 2 ). Patients in categories I and IIa have limbs that are not immediately threatened and should be considered for fibrinolytic therapy. Those in category IIb must be carefully evaluated for the most expeditious method of restoring blood flow. Because lysis of even fresh thrombus often requires infusions of 3 hours or more, many investigators hesitate to attempt percutaneous intraarterial lytic therapy in patients with critical ischemia and deterioration of neuromuscular function because the activation of plasminogen may initially be slow. Additionally, as lysis begins to soften the thrombus, there may be distal embolization. These emboli will respond to continued therapy but will transiently worsen distal perfusion. Therefore, patients with advanced ischemia who have readily accessible, short thrombi may be better served by operative intervention if it can be performed expeditiously. Patients with more extensive thrombosis or involvement of smaller vessels not amenable to mechanical thrombectomy should be considered for percutaneous thrombolytic therapy. Patients in category III, with advanced ischemic changes and absent neurologic function, often require primary amputation.

TABLE 2

Clinical Categories of Acute Limb Ischemia

Description and Prognosis	FINDINGS		DOPPLER SIGNALS
Description and Prognosis	Sensory Loss	Muscle Weakness	Arterial	Venous
I. Viable
Not immediately threatened	None	None	Audible	Audible
II. Threatened
a. Marginal
Salvageable if promptly treated	Minimal (toes) or none	None	(Often) inaudible	Audible
b. Immediate
Salvageable with immediate revascularization	More than toes, associated with rest pain	Mild, moderate	(Usually) inaudible	Audible
III. Irreversible
Major tissue loss or permanent nerve damage is inevitable	Profound, anesthetic	Profound, paralysis (rigor)	Inaudible	Inaudible

Lytic therapy provides the greatest benefit for patients with diffuse thrombosis of the native arteries associated with significant ischemia, such as that which occurs with acute occlusion of both the superficial and deep femoral arteries, as well as thrombosis of a distal graft or popliteal aneurysm with extension into the distal vessels. Thrombolysis is also preferred for the treatment of late thrombosis of a saphenous vein bypass graft because this method of therapy permits removal of clot and the identification of stenotic lesions without the associated flow surface damage induced by mechanical thrombectomy. Conversely, late thrombosis confined to an expanded polytetrafluoroethylene (ePTFE) graft can be rapidly extracted by surgical thrombectomy through a small incision. In these patients, percutaneous thrombolysis provides little additional benefit over open, mechanical thrombectomy.

Once thrombolytic therapy is considered, the risk that this treatment imposes for each patient must be assessed. There are few absolute contraindications to the use of lytic agents ( Box 1 ). The most obvious is the risk of serious bleeding at a site remote from the target. The presence of active bleeding or a bleeding diathesis from a known lesion, such as an intracranial aneurysm or lesion, peptic ulcer, or retinal pathologic finding, are generally regarded as contraindications to lytic therapy. Other factors, such as a recent operation or poorly controlled hypertension, are considered relative contraindications. In these instances, use of thrombolytic agents must be based on the clinical judgment of the physician caring for the patient.

BOX 1

Contraindications to Lytic Therapy

Absolute

Active bleeding
Recurrent gastrointestinal bleeding
Recent intracranial or spinal operation
Known intracranial pathologic condition (aneurysm, parenchymal injury)

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here