Local and systemic thrombolytic therapy for acute deep venous thrombosis

This article presents a review of the treatment of lower-extremity deep venous thrombosis (DVT) with systemic and catheter-directed thrombolysis (CDT) and percutaneous mechanical thrombectomy (PMT). Standard treatment including anticoagulation therapy and compression stockings may not be entirely adequate, because a significant proportion of patients eventually develop post-thrombotic syndrome (PTS). Thrombolytic agents might offer a potential advantage because they cause faster and more complete clot resolution, which may reduce or prevent residual vein stenosis and valve damage. Thrombolytic therapy results in greater lysis, but also in higher complication rates than does anticoagulation alone. Major bleeding occurs in 11% of patients treated with thrombolytic therapy. The incidence of PTS tends to be lower in patients treated with thrombolytics. However, several methodological flaws limit the conclusions with respect to reduction in PTS. No adequate randomised controlled trials have been performed comparing CDT or PMT with conventional therapy. Given the current data, thrombolytic treatment, CDT or PMT should not be applied except in extraordinary cases. First, the long-term effectiveness in terms of reducing PTS, although possible, remains uncertain. Second, the risks of thrombolytic therapy and PMT are higher. Third, current conventional therapy is relatively inexpensive, convenient and safe.     

Coronary thrombolysis with clot-selective plasminogen activators

Coronary thrombolysis is at present intensively investigated in the treatment of acute myocardial infarction. One line of research focuses on the development of new, fibrin-specific agents which might induce more clot-selective thrombolysis than streptokinase and urokinase. Clot-selective thrombolytic agents preferentially activate fibrin-bound plasminogen and, thereby, minimize the generation of free circulating plasmin which is responsible for the hemostatic breakdown and bleeding risk. Intravenous administration of fibrin-specific thrombolytic agents has two major advantages over intracoronary administration: firstly, infusion is more easily and widely applicable and secondly, therapy may be initiated more rapidly, which is important for the early restoration of nutritional blood flow and salvage of functional myocardial tissue. Three clot-selective thrombolytic agents are presently investigated for coronary thrombolysis. Impressive reopening rates have been reported with acylated streptokinase-plasminogen complex, but unfortunately, its use was associated with extensive systemic fibrinolytic activation and bleeding complications. Pro-urokinase, the single chain precursor of urokinase, exhibited intrinsic, fibrin-specific thrombolytic activity in vitro and in animal models but no human trials have yet been reported. At present, the largest clinical experience has been obtained with tissue-type plasminogen activator (t-PA). After small-scale pilot studies with t-PA obtained from cell culture media, larger clinical trials have now been performed using t-PA obtained by recombinant DNA technology (rt-PA). In the first study, intravenous infusion of rt-PA in patients with acute myocardial infarction yielded a recanalization rate of about 75% without clinically relevant systemic activation of the fibrinolytic system in most patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ultrasound-enhanced thrombolysis

Problems with current thrombolytic therapy include slow and incomplete thrombolysis and frequent bleeding complications. Increasing evidence from in vitro, animal, and initial patient studies indicates that application of ultrasound as an adjunct to thrombolytic therapy offers unique potential to improve effectiveness and decrease bleeding complications. Numerous studies in vitro demonstrate that low intensity ultrasound increases enzymatic fibrinolysis through mechanisms that include improving drug transport, reversibly altering fibrin structure, and increasing tPA binding to fibrin. These observations have been confirmed in animal models that demonstrated that ultrasound delivered transcutaneously or with an endovascular catheter accelerates thrombolysis in models of venous, arterial, and small vessel thrombosis. Ultrasound delivered at higher intensities using either an endovascular vibrating wire or transcutaneously in conjunction with stabilized microbubbles can cause mechanical fragmentation of thrombus without administration of plasminogen activator. Recent studies indicate that ultrasound at lower frequencies in the range of 20-40 kHz has a greater effect on thrombolysis with improved tissue penetration and less heating. These studies form the basis for clinical trials investigating the potential of ultrasound as an adjunct to improve thrombolytic therapy.     

Local and systemic thrombolytic therapy for acute venous thromboembolism

Thrombolytic therapy unquestionably leads to more rapid and complete clot lysis with a significantly higher risk of bleeding when compared with anticoagulation. The most definite indication for thrombolytic therapy in patients with VTE is massive PE associated with hemodynamic instability. Other potential indications, although not widely accepted or proven, include PE-related respiratory failure with severe hypoxemia and massive iliofemoral thrombosis with the risk of phlegmasia cerulea dolens. Routine use of thrombolytic therapy in all other cases of PE and DVT cannot be justified. Future research using randomized controlled studies should focus on the following key questions: Do hemodynamically stable patients with PE and right ventricular dysfunction benefit from thrombolysis, and, if so, is there a subset of patients within this group who are most likely to benefit? Does thrombolytic therapy improve long-term outcomes of DVT with a favorable risk-to-benefit ratio, and, if so, which patients are most likely to benefit long-term? What is the precise role of catheter-directed thrombolysis in the treatment of VTE, particularly the use of a low-dose thrombolytic agent in conjunction with mechanical clot disruption to minimize bleeding in patients at high risk? Until these questions are answered, clinicians must approach decision-making regarding the use of thrombolytic therapy in PE and DVT with careful consideration of the potential risks and benefits for the patient within the framework of currently available data.     

Thrombolytic therapy for arterial thrombosis.

The major development in the field of intra-arterial thrombolytic therapy over the past year was the publication of the phase II results of the Thrombolysis or Peripheral Arterial Surgery study, which compared the safety and efficacy of catheter-directed thrombolysis and surgery as the initial treatment of acute arterial occlusion. The results are consistent with those of the prior two studies, showing little or no difference between surgery and thrombolysis in the most important endpoints of survival and amputation rate. Patients receiving thrombolysis needed fewer interventions, but this benefit was balanced by increased bleeding complications. Additional studies have, therefore, been aimed at identifying subsets of patients with acute arterial occlusion who are most likely to benefit from thrombolysis. These studies have refined the selection criteria for use of thrombolytic therapy over the past year. In addition, studies have been published evaluating new drug doses and regimens aimed at broadening the scope of thrombolytic therapy in patients with acute arterial occlusion.     

Pharmacomechanical thrombolysis of acute and chronic symptomatic deep vein thrombosis: a systematic review of literature

Pharmacomechanical thrombolysis (PMT) is an emerging treatment option for symptomatic deep vein thrombosis (DVT). This may obviate the need for systemic or catheter-directed thrombolysis. PubMed, EMBASE, and Cochrane database search of PMT in acute and chronic symptomatic DVT was undertaken. Baseline demographic and clinical characteristics, procedural details, DVT characteristics, and procedural and clinical outcomes are presented. A total of 8 case series (n = 2528; 1998-2009) qualified for inclusion. Lower extremity symptomatic DVTs constituted the majority of the cases (>80%). Both acute (<14 days) and chronic (>14 days) DVTs were included. Procedural success was 59% to 100% and catheter-directed thrombolysis was used as an adjunct in 16% to 53%. No deaths or major bleeding complications were reported. Pharmacomechanical thrombolysis leads to the immediate resolution of clinical symptoms of DVT in the majority of patients. Pharmacomechanical thrombolysis may be a safe and novel method, when appropriate expertise and resources are available, for the treatment of symptomatic acute and chronic DVT.     

Percutaneous site-specific pharmacomechanical thrombolysis- thrombectomy system for bilateral acute limb ischemia

Acute limb ischemia (ALI) remains a life-threatening condition. Studies with catheter-directed thrombolysis and percutaneous mechanical thrombectomy systems show modest improvements in mortality compared to surgery but with pitfalls of major bleeding, distal embolization, recurrent thrombosis, prolonged thrombolytic infusion and increased overall cost. We present a unique and therapeutically challenging case of bilateral acute lower limb ischemia that was managed percutaneously in one setting by a novel technique using site-specific (isolated) pharmaco-mechanical thrombolysis-thrombectomy (IPMT) system.     

Synergism of thrombolytic agents in vivo

The existence of significant synergism between tissue-type plasminogen activator (t-PA) and single-chain urokinase-type plasminogen activator (scu-PA), and between t-PA and urokinase in thrombolysis in vivo is described. In a quantitative preparation of thrombolysis, consisting of rabbits in which a blood clot was induced in the jugular vein with 125I-labeled fibrin, intravenous infusion over 4 hr of t-PA, scu-PA, or urokinase in amounts of 0.5, 1.0, or 2.0 mg/kg body weight resulted in significant thrombolysis (30% to 60%). The simultaneous infusion of t-PA and scu-PA or of t-PA and urokinase had a significantly greater (p less than .001) thrombolytic effect than could be anticipated on the basis of the added effects of each agents alone. However, no synergism was observed between scu-PA and urokinase. The observed alpha 2-antiplasmin consumption and fibrinogen breakdown after urokinase at higher doses did not occur with the equivalent thrombolytic combinations of t-PA and urokinase. The combined use of synergic thrombolytic agents in patients may permit a significant reduction in total administered doses, probably with elimination of the systemic activation of the fibrinolytic system and the concomitant fibrinogen breakdown that is unavoidable with the currently used thrombolytic doses of each agent.     

Eptifibatide and risk of bleeding after failed thrombolysis

The safety of adjunct eptifibatide in the setting of rescue angioplasty (PTCA) with or without stenting after full-dose thrombolytic therapy is not well defined. Our study was undertaken to assess the risk of hemorrhagic complications following use of eptifibatide in patients undergoing rescue PTCA/stenting following failed thrombolysis. Clinical records of 43 consecutive patients (53% males) who received eptifibatide during rescue PTCA/stenting following full-dose fibrinolytic therapy were reviewed. Data were collected for: timing of rescue PTCA following fibrinolytic use; concomitant use of other antiplatelet agents; hospital length of stay; in-hospital mortality; and incidence of bleeding complications. Bleeding complications were categorized as major or minor according to Thrombolysis in Myocardial Infarction (TIMI) study group criteria. Overall bleeding complications developed in 13 patients (30%), with 4 patients (9%) experiencing major bleeding. Univariate predictors of major bleeding complications were: older age; female sex; lower baseline platelet count; and time to initiation of eptifibatide following failed thrombolysis. On multivariate analysis, the only predictors of bleeding were gender (27% in females versus 3% in males; odds ratio, 1.7; 95% confidence interval, 0.1-0.9) and time to initiation of eptifibatide following failed thrombolysis (4.6 +/- 2 hours versus 11 +/- 9 hours; p<0.04; 95% confidence interval, 2.1-11.4). Use of potent antiplatelet agents during rescue PTCA/stenting results in an increased risk of bleeding. Careful attention to predictors of bleeding and, in particular, delaying eptifibatide administration following full-dose fibrinolytic use may result in the reduction of major and minor bleeding complications.     

Successful Endovascular Removal of a Perforated Inferior Vena Cava Filter Complicated by a Large Retroperitoneal Hematoma: Pitfall of Catheter-Directed Thrombolysis

Symptomatic caval perforation is rare complication after inferior vena cava (IVC) filter insertion. A 44-year-old woman developed back pain after the placement of retrieval IVC filter during catheter-directed thrombolysis (CDT). Her computed tomography showed a large right-sided retroperitoneal hematoma. After 2 weeks, endovascular removal of the perforated filter was successfully performed without complication. Because thrombolytic agents can accelerate bleeding caused by endovascular procedures, the bleeding rate of the IVC filter deployment during CDT might be higher than expected.