Limited Fibrin Specificity of Tissue-type Plasminogen Activator and Its Potential Link to Bleeding (2023)

The benefit of catheter-directed thrombolysis for peripheral arterial occlusions is limited by hemorrhagic complications. Plasma fibrinogen level (PFL) has been suggested as a predictor of these hemorrhagic complications, but the accurateness of prediction is unknown. We summarized the available evidence on the predictive value of PFL for hemorrhagic complications after catheter-directed thrombolysis for acute or subacute peripheral native artery or arterial bypass occlusions.

We systematically searched PubMed and Embase until January 2016 for peer-reviewed publications on adults undergoing thrombolysis for acute or subacute peripheral native artery or arterial bypass occlusions, assessing the predictive value of PFL for hemorrhagic complications. Two authors independently performed data extraction. Risk of bias was assessed with the Quality in Prognosis Studies (QUIPS) tool.

In total, six studies (two randomized clinical trials and four cohort studies) reported on 613 patients undergoing 623 thrombolytic interventions for peripheral native artery or arterial bypass occlusions. No risk estimates for PFL and hemorrhagic complications were reported, two risk estimates were calculated, and nine associations between PFL and hemorrhagic complications were reported. For PFL<100mg/dL compared with ≥100mg/dL, the calculated relative risk was 0.33 (95% confidence interval, 0.05-2.25) for major bleeding and 1.39 (95% confidence interval, 1.06-1.81) for any bleeding. There were considerable differences in the time point of PFL measurement, the thrombolytic agents, the doses of the agents, and the definition of outcomes. PFL seems inaccurate in predicting hemorrhagic complications. Overall, the included studies were at high risk of bias.

Based on the current literature, the predictive value of PFL for predicting hemorrhagic complications after catheter-directed thrombolysis for acute or subacute peripheral native artery and arterial bypass occlusions is unproven.

Citation Excerpt :

By a pharmacological point of view, tenecteplase has been specifically bioengineered from alteplase to increase fibrin specificity, reduce binding to the physiological plasminogen activator inhibitor (PAI-1) and increase half-life [33]. Studies in experimental animals and in patients with venous thrombosis showed a lower bleeding risk with bolus alteplase in comparison to prolonged infusion of this agent, such correlating prolonged exposure to fibrin specific agents with an increased risk of bleeding [34–39]. The increased half-life of tenecteplase compared with alteplase, induces a prolonged exposure to this fibrin specific agent as well as a potentially prolonged overlapping between thrombolysis and anticoagulation.

The role of thrombolysis in hemodynamically stable patients with acute pulmonary embolism (PE) remains controversial. We performed a meta-analysis of randomized trials to assess the effect of thrombolysis in these patients.

We searched MEDLINE and EMBASE for randomized studies comparing thrombolysis and heparin for the initial treatment of hemodynamically stable PE patients. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated. NNH to cause a major bleeding (MB) or an intracranial hemorrhage (ICH) and NNT to avoid one death were also calculated.

Eleven studies (1833 patients) were included seven with rt-PA, three with tenecteplase and one with urokinase. Patients randomized to thrombolysis had a significant increased risk for MB (5.9% vs 1.9%; OR 2.83, 95% CI 1.68-4.76, I² 18.7%) and an increased risk for ICH (1.74% versus 0.6%; OR 2.36, 95% CI 0.98-5.71, I² 0%) and for fatal bleeding (1.3% versus 0.54%; OR 1.84, 95% CI 0.73-4.61, I² 0%). A not-significant reduction for all-cause death (1.74% vs 2.51%; OR 0.68, 95% CI 0.37-1.26, I² 0%) and a significant reduction for recurrent PE (1.1% vs 2.5%; OR 0.44, 95% CI 0.21-0.92, I² 0%) in favor of thrombolysis compared with heparin was found. NNH to cause a MB or an ICH were 27 and 91 patients, respectively. NNT to avoid one death was 125 patients.

Due to increased risk for MB and ICH with no evidence of reduction in mortality, thrombolysis should not be used for most normotensive PE patients.

To prospectively evaluate tenecteplase (TNK) for thrombolysis in acute lower-limb ischemia.

Forty-three consecutive limbs in 37 patients (15 male, 22 female) were treated for acute lower-limb ischemia. Group 1 included 22 limbs treated with TNK infusion of 0.25 mg/h and group 2 included 21 limbs treated with TNK at 0.125 mg/h. Technical success was defined by 95% clearing of thrombus, and clinical success was defined by Society of Interventional Radiology category for acute ischemia of +1. Complications were ranked by severity and relation to TNK administration. Logistic regression, Student t test, and analysis of variance were performed.

TNK infusions averaged 24 hours in duration (SD, 13 h), with means of 20 hours in group 1 and 27 hours in group 2 (P = .071). Technical success was achieved in 84% of limbs (36 of 43): 82% in group 1 (18 of 22) and 86% in group 2 (18 of 21; P = .827). The SIR ischemia category improved (ie, +1) in 86% of limbs (37 of 43), stayed the same (ie, category 0) in 12% of limbs (five of 43), and worsened (ie,+1) in 2% of limbs (one of 43). TNK-related complications were seen in 12% of limbs (n = 5) and were correlated with percentage decrease in fibrinogen level, initial TNK bolus, and abciximab administration (P = .001, P < .001, and P = .036, respectively). Initial TNK boluses of 1.5 mg or less were associated with fewer complications than boluses of 3–5 mg (P = .045). The percentage decrease in fibrinogen level in group 1 was 23% (SD, 29%), compared with 7% in group 2 (SD, 20%; P = .045). There was a 7% incidence of major bleeding complications (n > 3) and no intracranial hemorrhages.

Treatment of acute lower-limb ischemia with TNK infusion at 0.25 mg/h and 0.125 mg/h is associated with similar success and complication rates. TNK-related complications correlated with initial TNK bolus, abciximab treatment, and percent decrease in fibrinogen level. The initial TNK bolus dose should be limited to 1.5 mg.

Citation Excerpt :

The authors concluded that thrombolysis with urokinase appeared safer with urokinase than with rt-PA, with a lower incidence of hemorrhagic complications. Bleeding complications have been reported to be more frequent in patients given rt-PA compared with those given urokinase, perhaps because of its more pronounced effect in lowering fibrinogen; accumulation of large amounts of fragment X, a high molecular weight clottable fibrinogen degradation product; or its higher fibrin specificity and affinity.15-19 While retrospective reviews of data are limited in their ability to ascribe causality to seemingly consequential events, the findings of this analysis underscore the importance of focusing on underlying issues.

Over the past 2 decades the use of thrombolytic therapy in the management of peripheral occlusive diseases, most notably peripheral arterial occlusion (PAO) and deep venous thrombosis (DVT), has become an accepted and potentially preferable alternative to surgery. We examined the period when urokinase was in short supply and subsequently unavailable, to explore potential differences in clinical outcome and economic effect between urokinase and recombinant tissue plasminogen activator (rt-PA).

Data were obtained from the Premier Perspective Database, a broad clinical database that contains information on inpatient medical practices and resource use. The study population included all patients hospitalized in 1999 and 2000 with a primary or secondary diagnosis of PAO or DVT. Incidence was calculated for common adverse events, including bleeding complications, intracranial hemorrhage, amputation, and death. Cost data were also abstracted from the database, and are expressed as mean ± SD.

Demographic variables were similar in the urokinase and rt-PA groups. The rate of bleeding complications was similar in the urokinase and rt-PA groups. There were no intracranial hemorrhages in the urokinase group, compared with a rate of 1.5% in the rt-PA PAO group (P = .087) and 1.9% in the rt-PA DVT group (P = .175). The in-hospital mortality rate was lower in the urokinase-treated PAO subgroup (3.6% vs 8.5%; P = .026), but a similar finding in the DVT subgroup did not achieve statistical significance (4% vs 9.8%; P = .069). While pharmacy costs were greater in the urokinase-treated group ($5472 ± $5579 vs $3644 ± $6009, P < .001; PAO subgroup, $11,070 ± $15,409 vs $6150 ± $12,398, P = .003), overall hospital costs did not differ significantly between the 2 groups. This finding appears to be explained by a shorter hospital stay and reduced room and board costs in the urokinase-treated group.

There were significant differences in outcome in patients with PAO and DVT who received treatment with urokinase and rt-PA. While pharmacy costs were significantly greater when urokinase was used, reduction in length of stay accounted for similar total hospital costs compared with rt-PA. These findings must be considered in the context of the retrospective nature of the analysis and the potential to use dosing regimens that differ from those in this study.

To retrospectively evaluate reteplase in thrombolysis of peripheral arterial occlusion (PAO).

Forty limbs in 36 patients were treated with reteplase (0.5 U/h) with or without abciximab (bolus and 12-hour infusion). Twenty-four occlusions were in bypass grafts and 16 were in native arteries. Nineteen patients were treated with reteplase alone and 21 patients were treated with reteplase and abciximab. Chart review provided data from procedures and follow-up at 30 days and 6 months. Multivariable, analysis of variance, and Student t test comparisons of results and complications were performed.

Reteplase infusions averaged 31 hours in duration (range, 12–72 hours). The technical success rate was 80%. The clinical success rates were: immediate, 80%; 30-day, 65%; and 6-month, 45%. Major bleeding complications occurred in 20% of cases and intracranial hemorrhage occurred in 2.5%. The 6-month amputation-free survival rate was 78%. Major, minor, and lack of complications were statistically associated with mean decreases in fibrinogen levels from baseline of 72%, 46%, and 15%, respectively (P = .000013). Complications were not associated with length of infusion or use of abciximab (P = .77) Patients with grafts accounted for 89% of the major complications (eight of nine;)P = .009) and had worse clinical success immediately (71%), at 30 days (50%), and at 6 months (21%; P = .002, P = .003,k)P = .00001).

There was significant fibrinogen depletion with use of reteplase for PAO. The percent decrease in fibrinogen level correlates with lack of complications and incidence of minor and major complications. Abciximab use did not increase the complication rate. Thrombolysis of grafts is associated with increased incidence of complications and worse outcomes compared with thrombolysis of native arteries.

To determine the success and complication rates of intraarterial recombinant tissue-type plasminogen activator (rt-PA) infusion for the treatment of acute lower extremity artery and bypass graft occlusions.

The results of 74 limbs in 70 patients (mean age, 66 y) treated with catheter-directed rt-PA infusion for the treatment of acute lower extremity ischemia were retrospectively evaluated. The group included 42 bypass grafts and 32 native arteries. All limbs were viable at presentation. The mean duration of symptoms was 11.9 days. rt-PA was infused for a mean of 27.9 hours for a mean total dose of 38.7 mg. Initial infusion rates of 3–6 mg/h were lowered to a preferred rate of 1.5 mg/h. Thrombolytic success was defined as 95% thrombolysis of an occluded segment with return of antegrade flow. Major bleeding complications were defined as any hemorrhagic event leading to surgery, extended or unexpected hospitalization, transfusion, death, intracranial hemorrhage, or a decrease in hemoglobin of 5 g/dL or in hematocrit of 15%. Thirty-day mortality and amputation rates were calculated. Patient characteristics and infusion parameters were evaluated as to whether they contributed to thrombolytic success or major bleeding events.

Thrombolytic success was achieved in 64 limbs (86%). Major bleeding complications occurred in 33 (47%) patients. In 22 of these patients, bleeding occurred at a vascular puncture site, whereas remote bleeding occurred in seven patients. Remote bleeding complications included two retroperitoneal hematomas, two rectus sheath hematomas, one lower gastrointestinal hemorrhage, one episode of hemoptysis, and one dehiscence of a femoral-popliteal bypass graft revision. No parameters were found to be predictive of thrombolytic success, whereas a negative history of smoking, increasing duration of infusion, and a low preprocedural ankle-brachial index (ABI) were found to be associated with major hemorrhagic events. Four patients (6%) underwent amputation and one patient (1%) died, resulting in a 30-day amputation-free survival rate of 93%.

Catheter-directed rt-PA infusion is effective in achieving thrombolysis. Despite a significant number of bleeding complications, 30-day mortality and amputation rates were favorable. Nonetheless, complication rates related to bleeding were not trivial and further evaluation with use of variable dosing regimens is indicated.

Dental injury is the most common incident associated with anaesthesia. Regarding recent recommendations on informed consent and changes in airway management practices, a large series of claims related to dental injury has not been recently described. The aim of this study was to analyse a recent database in order to describe the characteristics of dental injury in France.

A database that prospectively collected claims reported to Le Sou Médical-MACSF between January 2003 and December 2010, was analysed. Five hundred and ninety-two cases were reported. The following characteristics were analysed: number and type of teeth injured, mechanism of injury, anaesthetic procedure, risk factors and dental outcome after injury.

Amongst the 1514 claims related to anaesthesia, 592 (39.2%) were classified as dental damage. Preoperative informed consent concerning possible perioperative dental injury was documented in only 34.8% of patients. Only one tooth was affected in 65.2% of patients, dental bridge injury in 12.8% of cases and damage to two or more teeth in 14% of patients. Incisors were involved in 50% of cases. Fracture was the most common type of injury (64.2%). Poor dentition was the most common risk factor (23.1%) followed by difficult intubation (15.4%). Both risks were combined in only 7.6% of cases. Tracheal intubation was the highest risk procedure (41.6%).

Dental injury remains the most common anaesthesia-related claim. Dental examination and documentation in patient medical files requires improvement and better informed consent on dental injury risk needs to be provided to patients.