Thrombolytic therapy (TT) using low-dose, slow, and ultra-slow infusions of tissue-type plasminogen activator (tPA) has become an established first-line treatment for prosthetic valve thrombosis (PVT). However, PVT with stuck valves represents a distinct clinical entity requiring tailored management. This study aimed to evaluate the effectiveness and safety of sequentially combining different TT regimens in patients with PVT and stuck valves. We enrolled 52 patients with PVT and stuck valves [female: 34 (65.4%), mean age: 47.5 ± 12.4 years] who underwent TT with sequential administration of slow (25 mg/6 h) and ultra-slow (25 mg/25 h) low-dose tPA regimens, based primarily on New York Heart Association (NYHA) functional class. All patients were assessed with cinefluoroscopy, transthoracic echocardiography, and transesophageal echocardiography. TT was successful in 46 patients (88.4%), with a median cumulative tPA dose of 120 mg (96–175). Major complications occurred in 3 patients (5.7%), including 1 cerebrovascular accident, 1 intracranial hemorrhage, and 1 gastrointestinal bleed requiring transfusion, while 6 patients (11.5%) experienced minor complications. One in-hospital death occurred (1.9%). Increased thrombus area was the only independent predictor of both failed TT and adverse events. A moderate positive correlation was observed between thrombus area and total tPA dose (r = 0.479; p < 0.001). In conclusion sequential use of slow and ultra-slow low-dose tPA infusion appears to be a safe and effective strategy for managing PVT with stuck valves. Nevertheless, patients with larger thrombus burden remain at increased risk for treatment failure and complications.
Mechanical bileaflet prosthetic valves are widely implanted because of their favorable hemodynamic profile and low structural complication rates. Despite these advantages, prosthetic valve thrombosis (PVT) remains a serious problem associated with substantial morbidity and mortality. , Even partial immobilization of a leaflet can cause clinically significant obstruction, most commonly due to thrombus, although pannus formation may also impair leaflet motion. , Clinical presentation ranges from mild symptoms to acute hemodynamic collapse. Imaging modalities including transthoracic echocardiography (TTE), 2-dimensional and real-time 3-dimensional transesophageal echocardiography (TEE), cinefluoroscopy (CF), and multidetector computed tomography (MDCT) are essential for confirming the diagnosis and distinguishing thrombus from pannus. ,,,, Although emergency surgery was traditionally the preferred approach, high operative risk, particularly in unstable patients, has led to increasing use of thrombolytic therapy (TT), supported by expanding evidence and reflected in current guidelines. Low-dose slow-infusion and, more recently, ultra-slow infusion protocols of tissue-type plasminogen activator (tPA) have shown improved safety and effectiveness compared with earlier high-dose regimens. ,,,, Contemporary AHA/ACC and ESC/EACTS guidelines endorse TT as a first-line option in selected patients, emphasizing individualized risk-based management. , PVT with stuck valves represents a challenging subgroup requiring careful therapeutic balance. The present study aimed to investigate the effectiveness and safety of sequentially combining slow and ultra-slow low-dose tPA infusion regimens in patients with PVT and stuck valves, guided by CF and TEE imaging.
Methods
Study population
Between January 2009 and December 2024, 52 PVT patients with stuck leaflets [female: 34 (65.4%), mean age: 47.5 ± 12.4] who underwent TT with sequential combination of slow and ultra-slow infusion of low dose t-PA regimens were enrolled in this multicenter study. Specifically, a total of 66 patients were initially screened for eligibility, and 14 patients were excluded based on predefined exclusion criteria including a contraindication to TT (3 patients), obstructive pannus formation (2 patients), unstable hemodynamic status or cardiogenic shock (5 patients), end stage liver and renal disorders (1 patient), active infection, acute coronary syndrome (2 patients), renal insufficiency, chronic inflammatory disease, deep vein thrombosis, coagulopathy and malignancies (1 patient). Complete blood count and blood chemistry panel were carried out in all patients at the time of admission. The patient demographic characteristics, medical history, elapsed time since valve surgery, type and position of the prosthetic valve, rhythm disorders, New York Heart Association (NYHA) functional class, leading symptoms, and international normalization ratio (INR) values at the time of admission were prospectively entered into a database. All patients provided a written informed consent and the study protocol was approved by the local ethics committee of the hospital in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Echocardiography
All patients underwent TTE performed by using iE33 echocardiography device (Philips Medical Systems, Andover, Massachusetts), and S5-1 sector array transducer with the patient in the left lateral decubitus position. Parasternal long axis and short axis views and apical 5 chamber view were used during TTE evaluation. Left atrial diameter were measured on the parasternal long-axis view. Left ventricular ejection fractions of the patients were calculated by using biplane Simpson’s method. Following TTE, 2D and RT-3D TEE studies were performed in all patient by using an X7-2t transducer on an iE33 ultrasound machine (Philips Medical Systems, Andover, Massachusetts). The presence of obstruction was defined on the basis of Doppler echocardiographic measurements (peak velocity, mean gradient, effective orifice area, dimentionless index, and acceleration time as appropriate). The cut-off values for these Doppler parameters were defined based on the recent recommendations.
Thrombus was recognized as a homogeneous, mobile, or fixed mass with similar echo density to the myocardium located at the valve occluder and/or valve struts and was visualized in all patients with PVT using echocardiography. The largest thrombus area was measured by 2D TEE between 0° and 180° angles where there was less interference with acoustic shadowing ( Figure 1 ). In the presence of a single mass the thrombus was traced, otherwise each thrombi was traced separately and the thrombus areas were finally summed-up. ,,,
Serial 2D transesophageal echocardiographic views demonstrating progressive thrombus resolution and restoration of leaflet motion. (A) Large obstructive thrombus attached to the prosthetic valve at baseline. (B) Early reduction in thrombus area following the initial thrombolytic session. (C) Further decrease in thrombus burden and improved visualization of leaflet motion after subsequent therapy. (D) Marked reduction in thrombus with near-complete restoration of leaflet mobility (arrow).
A diagnosis of pannus formation was made based on the presence of fixed, bright, echodense structures, sometimes containing focal calcific deposits, narrowing circumferentially the inflow and outflow orifices of the prosthesis on 3D TEE images. ,, Discrimination between obstructive pathologies such as pannus or thrombus was mainly based on 2D and RT-3D TEE studies in majority of the patient population. In several patients, MDCT was performed in the differential diagnosis between pannus and thrombus. , Patients with obstructive pannus formation alone or accompanied by PVT were excluded from the study.
Cinefluoroscopy
All bileaflet valves were directly visualized by using a tangential view during CF. The opening and closing angles of the disks were measured as the angular distance between the 2 leaflets in the fully open and closed position, and values of 3 consecutive cardiac cycles were averaged. These angles were compared to the normal manufacturer angles for each individual valve types. Stuck valve status was defined as persistent and complete restricted motion of a single leaflet with a measured opening angle lower than the reference values.
Rationale for TT
After diagnostic confirmation of PVT by 2D and RT-3D TEE, patients with cardiogenic shock were excluded and referred to immediate surgery. Based on the previous reports regarding the safety and effectiveness of low-dose slow-infusion TT protocol, ,, in the absence of contraindications, a TT regimen with 6 hours infusion of 25 mg t-PA without a bolus (repeat up to 6 times if needed, maximum total dose of 150 mg) was administered as a first-line therapy to NYHA functional class III-IV patients with obstructive PVT and stuck valves according to the protocol described previously. All patients underwent serial TTE, 2D TEE ( Figure 1 ), real-time 3D TEE ( Figure 2 ), and CF ( Figure 3 ) examination between each TT sessions. TT sessions with low-dose slow-infusion of tPA were repeated until a partial or complete resolution of the stuck leaflet was observed in CF. Immediate 2D and RT-3D TEE was performed in patients when a partial or complete resolution of the stuck leaflet was observed. In patients meeting the criteria for complete success and in patients with partial success and a residual thrombus size <10mm, TT was interrupted and anticoagulation with unfractinated heparin (UFH) and warfarin was initiated. TT was continued with low-dose ultra-slow infusion of tPA up to 200 mg in patients with partial success with a residual thrombus size ≥10mm under the guidance of serial TEE examinations between the sessions according to the protocol described previously. Anticoagulation was initiated in these patients after complete or partial success. Endovascular catheter-directed thrombolysis was not used in any patient; all subjects were treated exclusively with systemic low-dose slow or ultra-slow infusion protocols.
Real-time 3D transesophageal echocardiographic images showing sequential reduction of thrombus burden during thrombolytic therapy. (A) Baseline 3D en face view demonstrating circumferential thrombus surrounding the prosthetic valve. (B) Partial regression of thrombus after initial therapy. (C) Continued decrease in thrombus volume with improved visualization of the occluder mechanism. (D) Near-complete thrombus resolution with restoration of leaflet motion (arrows).
Serial cinefluoroscopic images illustrating mechanical leaflet function during thrombolytic therapy. (A) Baseline fluoroscopy demonstrating a stuck leaflet (arrow). (B) Initial improvement in leaflet excursion following therapy. (C) Further restoration of leaflet opening angle. (D) Complete recovery of leaflet mobility after successful thrombolytic therapy (arrow).
In patients with NYHA functional class I-II, a TT regimen with 25 hours infusion of 25 mg t-PA without a bolus (repeat up to 8 times if needed, maximum total dose of 200 mg) was administered as a first-line therapy. Patients underwent serial TTE and CF after each 12 hours and immediate 2D and RT-3D TEE was performed in patients when a partial or complete resolution of the stuck leaflet was observed. In patients meeting the criteria for complete success and in patients with partial success and a residual thrombus size <10mm, TT was interrupted and anticoagulation with UFH and warfarin was initiated. TT was continued with low-dose ultra-slow infusion of tPA up to 200 mg in patients with partial success with a residual thrombus size ≥10mm. Anticoagulation was initiated in these patients after complete or partial success.
In patients unresponsive to maximum doses of low-dose slow and ultra-slow infusion TT regimens, 24 hours infusion of 1.5 million units streptokinase (SKZ) was initiated and repeated up to 3 million units as needed according the protocol described previously. The status of leaflet motion was evaluated by serial CF imaging between TT sessions and patients with a partial or complete resolution of the stuck leaflet were referred to TEE examination. In patients who were still unresponsive to TT with SKZ, surgery was scheduled with regard to the clinical status of the patient.
Anticoagulation with intravenous unfractionated heparin was withheld during t-PA infusion due to increased risk of bleeding. UFH infusion, with a target of activated partial thromboplastin time (aPTT) between 1.5 and 2.5 times the control, was started immediately after TT sessions and administered for 6 hours between TT sessions. If repeated TT session was needed, UFH was withheld again until aPTT was less than 50 seconds.
In the absence of fatal and nonfatal major adverse events, (1) Doppler documentation of the complete improvement in valve hemodynamics, and complete normalization of leaflet mobility in CF, (2) reduction in major diameter and/or area of the thrombus by 75%, and (3) symptomatic improvement were considered as the major criteria for TT success in patients with obstructive PVT. Complete success was defined when all 3 criteria were met, and partial success was defined as less than 3. ,,,
Statistical analysis
Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 19.0. (IBM Corp. Armonk, NY). Descriptive statistics were reported as mean ± standard deviation for continuous variables with normal distribution or median (25 th–75 th percentiles) values for continuous variables without normal distribution and as frequency with percentages for the categorical variables. The Shapiro-Wilk test was used to test the normality of the distribution of continuous variables. Continuous variables were compared between groups using the Student’s t test or Mann- Whitney U test as appropriate. Categorical variables were compared using the Chi-square or Fisher’s exact test. Correlational analyses were performed using Pearson or Spearmen’s correlation tests as appropriate. A multivariate logistic regression analysis was performed in order to identify any independent associates of failed TT and adverse events. The significance level was accepted as p < 0.05 in all statistical analyses.
Results
The study population included 52 patients with PVT and stuck valves [female: 34 (65.4%), mean age: 47.5 ± 12.4 years]. Valve distribution was as follows: mitral in 40 patients (76.9%), aortic in 9 (17.3%), and tricuspid in 3 (5.8%). Stuck valve types consisted of 29 St. Jude Medical (55.8%), 11 Carbomedics (21.2%), 5 Sorin-Bicarbon (9.6%), and 7 ATS (13.5%) prostheses. The median time from valve surgery was 36 months (IQR: 21–72), and 17 patients (32.7%) had concomitant atrial fibrillation. Specifically, among the 52 patients, 39 (75%) had subtherapeutic anticoagulation within the previous 3 months, while the remaining 13 (25%) had other potential contributing factors including elevated fibrinogen levels (3 patient), positive anticardiolipin antibodies (2 patient), anti–tPA antibodies (5 patient), genetic or thrombophilia-related background (3 patient). On admission, 21 patients (40.3%) were in NYHA functional class I–II and 31 patients (59.7%) in class III–IV. The median thrombus area was 1.35 cm² (IQR: 0.9–1.7) ( Table 1 ).
Table 1
Baseline demographic, clinical and echocardiographic characteristics of the study population and comparisons regarding the success of thrombolytic therapy
| Parameters | All patients (n = 52) | Successful TT (n = 46) | Failed TT (n = 6) | p value |
|---|---|---|---|---|
| Age, (years) | 47.5 ± 12.4 | 47.4 ± 12.7 | 48.5 ± 11.2 | 0.843 |
| Gender, male n (%) | 18 (34.6%) | 17 (37%) | 1 (16.7%) | 0.326 |
| Stuck valve position, n (%) | ||||
| Mitral | 40 (76.9%) | 36 (78.3%) | 4 (66.7%) | 0.475 |
| Aortic | 9 (17.3%) | 8 (17.4%) | 1 (16.7%) | |
| Tricuspid | 3 (5.8%) | 2 (4.3%) | 1 (16.7%) | |
| Valve type, n (%) | ||||
| St Jude medical | 29 (55.8%) | 25 (54.3%) | 4 (66.7%) | 0.689 |
| Carbomedics | 11 (21.2%) | 10 (21.7%) | 1 (16.7%) | |
| Sorin-Bicarbon | 5 (9.6%) | 4 (8.7%) | 1 (16.7%) | |
| ATS | 7 (13.5%) | 7 (15.3%) | 0 (0%) | |
| ETSVS, (months) | 36 (21–72) | 34 (12–72) | 54 (25–84) | 0.267 |
| Atrial fibrillation, n (%) | 17 (32.7%) | 14 (30.4%) | 3 (50%) | 0.337 |
| LVEF, (%) | 52.3 ± 5.1 | 51.8 ± 6.4 | 49.5 ± 5.3 | 0.410 |
| Left atrial diameter, (mm) | 42.3 ± 3.9 | 41.7 ± 6.9 | 41.8 ± 2.1 | 0.978 |
| NYHA functional class, n (%) | ||||
| I-II | 21 (40.3%) | 20 (43.5%) | 1 (16.7%) | 0.208 |
| III-IV | 31 (59.7%) | 26 (56.5%) | 5 (83.3%) | |
| INR on admission, n (%) | ||||
| Therapeutic | 13 (25%) | 12 (26.1%) | 1 (16.7%) | 0.616 |
| Subtherapeutic | 39 (75%) | 34 (73.9%) | 5 (83.3%) | |
| Thrombus area, (cm 2) | 1.35 (0.9-1.7) | 1.15 (0.9-1.6) | 2.4 (1.9-2.7) | < 0.001 |
| TT outcome, n (%) | ||||
| Successful | 46 (88.4%) | 46 (100%) | 0 (0%) | – |
| Failed | 6 (11.6%) | 0 (0%) | 6 (100%) | |
| Complications, n (%) | 9 (17.3%) | 5 (10.8%) | 4 (66.6%) | 0.006 |
| Intracranial bleeding | 1 (1.9%) | 0 (0%) | 1 (16.6%) | |
| GIS bleeding | 2 (3.8%) | 1 (2.2%) | 1 (16.6%) | |
| CVA | 1 (1.9%) | 0 (0%) | 1 (16.6%) | |
| TIA | 2 (3.8%) | 2 (4.3%) | 0 (0%) | |
| Epistaxis | 3 (5.7%) | 2 (4.3%) | 1 (16.6%) | |
| Mortality, n (%) | 1 (1.9%) | 0 (0%) | 1 (16.6%) | 0.115 |
| Total tPA dose, (mg) | 120 (96–175) | 110 (85–165) | 160(150–200) | 0.028 |
| Sessions with 25mg/6h tPA | 1 (0–2.75) | 1 (0–2) | 2.5 (1–6) | 0.098 |
| Sessions with 25mg/25h tPA | 3 (1.25–5) | 3 (2–5.25) | 1.5 (0–4.25) | 0.141 |
| Patients needed SKZ, n (%) | 5 (9.6%) | 2 (4.3%) | 3 (50%) | 0.008 |
| Patients needed surgery, n (%) | 2 (3.8%) | 0 (0%) | 2 (33.3%) | 0.011 |
Abbreviations: CVA = cerebrovascular accident; ETSVS = elapsed time since valve surgery; GIS = gastrointestinal system; INR = international normalized ratio; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; SKZ = streptokinase; TIA = transient ischemic attack; tPA = tissue-type plasminogen activator; TT = thrombolytic therapy.
Bold p values statistically significant p < 0.05.
TT outcomes
Patients in NYHA functional class I–II received first-line ultra-slow infusion of 25 mg tPA over 25 hours, while patients in class III–IV received slow infusion of 25 mg tPA over 6 hours, continued with ultra-slow infusion if needed ( Figure 4 ). The median number of slow-infusion sessions was 1 (IQR: 0–2.75), and the median number of ultra-slow sessions was 3 (IQR: 1.25–5).
