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Background: Optimal first-trimester anticoagulation is still challenging in pregnant women with mechanical heart valves (MHVs) requiring high-dose warfarin. This multicenter prospective study aims to determine the optimal anticoagulation regimens for pregnant patients with MHVs., Methods: All women were allocated to one of three treatment options during first trimester including lone low-molecular-weight heparin (LMWH), combination of LMWH + 2.5 mg warfarin, and LMWH+4 mg warfarin. Primary maternal outcome included a combination of death, thromboembolism, severe bleeding, and need for treatment of mechanical valve thrombosis (MVT). Any fetal loss was determined as primary fetal outcome., Results: The study included 78 pregnancies in 65 women with MHVs. Primary maternal outcome rate was 44%, 12.5%, 3.5%, respectively. The rates of primary maternal outcome (44 vs 3.5%, P < .001), obstructive MVT (16 vs 0%, P = .04), MVT requiring treatment (28 vs 0%, P = .003), and cerebral embolism (24 vs 3.4%, P = .041) were found to be significantly higher in lone LMWH group compared to LMWH + 4 mg warfarin group. Moreover, the rates of primary maternal outcome (12.5 vs 44%, P = .015) and treatment for MHV thrombus (4.2 vs 28%, P = .049) were significantly lower in LMWH + 2.5 mg warfarin group compared to lone LMWH group. The incidences of fetal loss were 8 (32%) in the lone LMWH group, 8 (33.3%) in LMWH + 2.5 mg warfarin group, and 11 (37.9%) in LMWH + 4 mg warfarin group (P = .890 for 3-group).Warfarin related-embryopathy was not observed in any case., Conclusions: The combined anticoagulation strategy of LMWH plus low-dose warfarin during the first trimester of pregnancy may result in less maternal complications with comparable fetal outcomes in patients with MHVs., Condensed Abstract: Low-molecular-weight heparin (LMWH) is thought to be safer for the fetus, however it is suspected to be less protective for the mother. To solve this dilemma, the authors suggested a novel anticoagulation strategy in pregnant women with prosthetic valves. Seventy-eight pregnancies of 65 women (median age 32 [27-35] years) were included in the study. A combination of LMWH and a reduced dose warfarin were associated with low rates of thrombus-related complications in pregnant patients with mechanical heart valves., Competing Interests: Conflict of interest All of the authors have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Intermittent malfunction is a rare but potentially serious complication of prosthetic heart valve replacement. This study aimed to describe the clinical features and etiologic causes of patients with intermittent mechanical prosthetic heart valve dysfunction., Methods: Between 2010 and 2021, 16 patients who were evaluated in the echocardiography laboratory of Koşuyolu Training and Research Hospital with the diagnosis of intermittent malfunction of prosthetic valves were included in the study., Results: The evaluated patients consisted of 12 bi-leaflet mitral valve replacements and 2 mono-leaflet mitral valve replacements. The underlying causes of intermittent malfunction were classified as follows: residual chord (n=4), obstructive thrombus (n=2), non-obstructive thrombus (n=2), vegetation (n=2), pannus and obstructive thrombus coexistence (n=1), and solely pannus (n=1). One of the patients with mono-leaflet mitral valve replacements had pannus and obstructive thrombus. In the other patient with mono-leaflet mitral valve replacement, a stuck valve was observed in 1 of 12 beats secondary to arrhythmia. There were also 2 patients with aortic valve replacements. One patient had moderate aortic regurgitation due to prominent calcification and the other had moderate obstruction due to pannus. In the patient with pannus, a stuck leaflet was observed in 1 of 6 beats and moderate aortic regurgitation arose in 1 of 2 beats in the patient with calcification., Conclusions: The intermittent stuck valve may have catastrophic outcomes. When making a treatment decision in these patients, assessing the degree of regurgitation or stenosis is essential. In particular, the frequency of entrapment should be taken into consideration when deciding the optimal therapy for intermittent prosthetic heart valve dysfunction.

Background: Prosthetic valve thrombosis (PVT) is one of the life-threatening complications of prosthetic heart valve replacement. Due to the lack of randomized controlled trials, the optimal treatment of PVT remains controversial between thrombolytic therapy (TT) and surgery., Objectives: This study aimed to prospectively evaluate the outcomes of TT and surgery as the first-line treatment strategy in patients with obstructive PVT., Methods: A total of 158 obstructive PVT patients (women: 103 [65.2%]; median age 49 years [IQR: 39-60 years]) were enrolled in this multicenter observational prospective study. TT was performed using slow (6 hours) and/or ultraslow (25 hours) infusion of low-dose tissue plasminogen activator (t-PA) (25 mg) mostly in repeated sessions. The primary endpoint of the study was 3-month mortality following TT or surgery., Results: The initial management strategy was TT in 83 (52.5%) patients and surgery in 75 (47.5%) cases. The success rate of TT was 90.4% with a median t-PA dose of 59 mg (IQR: 37.5-100 mg). The incidences of outcomes in surgery and TT groups were as follows: minor complications (29 [38.7%] and 7 [8.4%], respectively), major complications (31 [41.3%] and 5 [6%], respectively), and the 3-month mortality rate (14 [18.7%] and 2 [2.4%], respectively)., Conclusions: Low-dose and slow/ultraslow infusion of t-PA were associated with low complications and mortality and high success rates and should be considered as a viable treatment in patients with obstructive PVT., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

It was previously observed that two dimensional (2D) Doppler derived and real-time three-dimensional (RT-3D) directly measured valve areas were smaller than reported manufacturer sizes. It may be helpful to obtain the ranges of inner diameters (IDs) and the geometric orifice area (GOA) during evaluation of prosthetic mitral valves. In this study, we aimed to provide reference dimensional parameters of bileflet mitral mechanical prosthetic valves. Patients with recent mitral valve replacement were examined by 2D and RT-3D transesophageal echocardiography (TEE) in the early postoperative period when the presence of pannus overgrowth was unlikely. Measurements of 2D IDs, 3D hinge to hinge (HHD) and edge to edge diameters (EED) and 3D GOA were obtained and compared with reported manufacturer sizes and areas. This study enrolled 126 patients with mitral prosthetic valves (38 ATS, 42 Carbomedics, 46 St. Jude Medical, all bileaflet). The measured 2D and 3D IDs and GOA were significantly smaller than reported manufacturer sizes in the majority of the valve sizes. This RT-3D TEE-guided study provides ranges of reference values for directly measured IDs and GOA of the three most commonly used mechanical mitral prosthetic valve types for the first time in a relatively large series.

Objective: Prosthetic valve thrombosis (PVT) is a serious complication among patients with prosthetic heart valves. Thrombolytic therapy (TT) is now widely used as first-line treatment for PVT. Endothelial dysfunction has previously been reported in patients with PVT. The aim of this study was to investigate the changes in endothelial function soon after TT in PVT patients., Methods: The study group included 85 patients with PVT [female: 53 (62.3%); age: 48.7±13.9 years] who were evaluated prospectively before and shortly after TT. All of the patients were evaluated using transthoracic and transesophageal echocardiography. TT was administered in all cases with a low-dose, ultra-slow infusion regimen. Endothelial function was evaluated using a noninvasive measurement of flow-mediated dilatation (FMD) of the brachial artery during reactive hyperemia., Results: The study population included 38 (44.7%) obstructive and 47 (55.3%) non-obstructive PVT patients. The obstructive PVT patients had lower baseline FMD values than the non-obstructive PVT group (5.31±0.76% vs. 5.87±0.84%; p=0.003). TT was successful in 79 patients (92.9%). FMD was significantly increased in the successfully thrombolyzed patients after TT (5.65±0.86% vs. 7.13±1.26%; p<0.001). There was no significant difference in the FMD values after TT in patients who were unresponsive to TT (5.07±0.61% vs. 5.38±0.95%; p=0.371). There was a significant increase in FMD values after TT in patients with obstructive PVT (5.31±0.76% vs. 8.22±1.15%; p<0.001). However, this difference was not statistically significant for patients with non-obstructive PVT (5.87±0.84% vs. 6.11±0.95%; p=0.276)., Conclusion: This study demonstrated that successful TT may contribute to improvement of impaired endothelial function in patients with obstructive PVT.

Mechanical prosthetic heart valves (MPHVs) are highly thrombogenic, and a pregnancy-induced procoagulant status increases the risk of MPHV thrombosis. Despite numerous case reports, 2 major registries and meta-analyses/systematic reviews, optimal anticoagulation therapy during pregnancy remains controversial. The goal of this study was to evaluate different anticoagulation regimens in pregnant patients with MPHVs. The outcomes of anticoagulation regimens were assessed retrospectively in pregnant women (110 women; 155 pregnancies) with MPHVs. The study population was divided into 5 groups according to anticoagulation regimens used; high-dose warfarin (>5 mg/d) throughout pregnancy (group 1), low-dose warfarin (≤5 mg/d) throughout pregnancy (group 2), low molecular weight heparin (LMWH) throughout pregnancy (group 3), first trimester LMWH, 2nd and 3rd trimester warfarin (group 4), first 2 trimester LMWH, and 3rd trimester warfarin (group 5). Of 155 pregnancies, 55 (35%) resulted in fetal loss; whereas 41 (27%) cases with abortion (miscarriage and therapeutic) and 14 (9%) stillbirths occurred. The comparison of the groups showed that the whole abortion rates including therapeutic abortion were significantly higher in Group 1, and lower in groups 3 and 5 (p <0.001). However, miscarriage rates were similar between the groups. A total of 53 pregnancies (34%) suffered from prosthetic valves thrombosis (PVT) during pregnancy or in the postpartum period. Group 2 had significantly lower rates of PVT than the other groups (p <0.001). In conclusion, the current data suggests that there is no optimal therapy, and that all managements have advantages and disadvantages. Low-dose warfarin (≤5 mg/day) regimen with therapeutic international normalized ratio levels may provide effective maternal protection throughout pregnancy with acceptable fetal outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Spontaneous echo contrast (SEC) is defined as dynamic, smoke-like echoes within the cardiac cavities with a characteristic swirling motion seen on echocardiography. Clinical studies have demonstrated that SEC is a risk factor for left atrial thrombus formation and an important indicator for potential systemic embolism. Platelet indices have been associated with the presence of SEC in patients with mitral stenosis. The aim of this study was to investigate the relationship between platelet indices and SEC in patients with prosthetic heart valves., Methods: A total of 89 patients [female: 38 (42.4%); median age: 52 years (range: 36-67 years)] with SEC formation in the left atrium, and 257 control subjects [female: 123 (47.5%); median age: 56 years (range: 45-65 years)] without SEC formation were enrolled. All of the patients were evaluated by using transthoracic and transesophageal echocardiography. Laboratory tests including complete blood count and biochemical parameters were analyzed., Results: Patients with SEC formation had more frequent atrial fibrillation, higher left atrial diameter (LAD) and lower left ventriular ejection fraction values. Platelet indices including platelet count, platelet distribution width, mean platelet volume, and plateletcrit did not differ between the groups. Increased LAD was detected as the only independent predictor of SEC development., Conclusion: Platelet indices were not found to be associated with the presence of SEC formation in the left atrium among patients with mitral prosthetic valves. Therefore, the use of platelet indices alongside known echocardiographic and clinical risk factors to predict SEC development in patients with a mitral prosthesis is debatable.

The past 65 years have witnessed remarkable progress in the development of safe, hemodynamically favorable mechanical heart valves. Today, there are a large number and variety of prostheses in use and many prostheses have been used for a while and then discontinued. When patients lack reliable information about their heart valve prostheses, identification of valve model becomes difficult even for specialized physicians in this area. A combination of cinefluoroscopy and echocardiography makes it possible to provide accurate and detailed information regarding identification of prosthetic valve models. Fluoroscopic examination is a useful technique to evaluate patients following mechanical heart valve replacement. However, transthoracic echocardiography and transesophageal echocardiography have almost replaced cinefluoroscopy in the evaluation of prosthetic heart valves. Especially, real-time three-dimensional transesophageal echocardiography provides distinctive images of prosthetic heart valves, particularly for those in the mitral position. A large body of literature has been published to familiarize physicians with the radiological appearance of numerous mechanical prostheses. However, there is a lack of data regarding the identification of prosthetic valve models based on echocardiographic appearance. In this review, we aimed to describe distinctive echocardiographic and cinefluoroscopic markers for identifying the type and brand of several commonly used mechanical prosthetic heart valves.

Intermittent malfunction is a rare but potentially serious complication of prosthetic heart valve (PHV) replacement. It may be observed in both mitral and aortic valve prosthesis and may lead to either paroxysmal obstruction or regurgitation, depending on the valve location and on the phase of the cardiac cycle during which the leaflet is entrapped. The most frequently encountered causes of intermittent valve malfunction are pannus formation, prosthetic valve thrombosis, vegetations, and remnants of subvalvular apparatus such as chordae tendineae and suture material. Intermittent severe regurgitation of PHV due to residual chordae tendineae is very rare clinical entity, and transesophageal echocardiography is an indispensable guide in the differential diagnosis. Here, we represent an interesting case of intermittent regurgitation of a mitral prosthetic valve due to entrapment by a residual subvalvular apparatus., (© 2018 Wiley Periodicals, Inc.)

Introduction: Procoagulant activity of heparanase has been recently described in several arterial and venous thrombotic disorders. In this study, we aimed to investigate the role of heparanase with regard to thrombus burden, thromboembolism, and treatment success with unfractionated heparin (UFH) in patients with prosthetic valve thrombosis (PVT)., Methods: This study enrolled 79 PVT patients who received UFH for PVT and 82 controls. Plasma samples which were collected from patients both at baseline and after the UFH treatment and from controls at baseline only, were tested for heparanase levels by heparanase enzyme-linked immunosorbent assay., Results: The PVT group included 18 obstructive and 61 non-obstructive PVT patients who received UFH infusions for a median duration of 15 (7-20) days. The UFH treatment was successful in 37 (46.8%) patients. Baseline heparanase levels were significantly higher in the patient group than in the controls [0.29 (0.21-0.71) vs. 0.25 (0.17-0.33) ng/mL; p = 0.002]. Baseline heparanase levels were significantly higher in obstructive PVT patients. There was a significant increase in heparanase levels after UFH treatment. Post-UFH heparanase levels were higher in patients who experienced treatment failure compared to successfully treated group. Baseline and post-UFH heparanase levels were significantly higher in patients with a thrombus area ≥1 cm 2 and with a recent history of thromboembolism., Conclusions: Increased heparanase levels may be one of the esoteric causes for PVT. UFH treatment may trigger an increase in heparanase levels which may affect the treatment success. Increased heparanase levels may be associated with high risk of thromboembolism and increased thrombus burden in PVT patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Coronary thromboembolism (CE) is a rare cause of prosthetic valve derived complications. This study investigates the diagnosis and treatment strategies for non-ST elevation acute coronary syndrome (NSTEACS) in patients with prosthetic heart valves. Forty-eight NSTEACS patients with prosthetic heart valves (mitral:27; aortic:14; mitral+aortic:7) were included in this study. All patients underwent transthoracic and transesophageal echocardiographic examination and coronary angiography. Normal coronary angiographic findings, or visible trombus in one of the coronary arteries, international normalized ratio <2, concomitant prosthetic valve thrombosis (PVT) and absence of multivessel atherosclerotic disease favored CE rather than atherothrombosis. Thrombolytic therapy (TT) with low-dose slow-infusion of tissue type plasminogen activator was used in patients with suspected CE and/or PVT. Coronary angiography demonstrated normal coronary arteries in 26 patients, CE in 16 patients and coronary atherosclerosis in 6 patients. Transesophageal echocardiography revealed obstructive PVT in 9 and nonobstructive PVT in 28 patients whereas 11 patients had normally functioning prostheses. TT was administered to 24 patients with PVT and/or CE. In these patients, TT was successful in 19 patients, partially successful in 4 patients and failed in 1 patient. In conclusion, NSTEACS in patients with prosthetic heart valves is more likely to be associated with PVT derived CE rather than atherosclerosis. TT with low-dose slow infusion of type plasminogen activator has proved its efficacy and safety in patients with CE and/or PVT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

: Plasma D-dimer level is an indicator of thrombosis and endogenous fibrinolytic activity. We investigated the association between the D-dimer levels and thrombus burden and cerebrovascular events in patients with obstructive prosthetic valve thrombosis (PVT). This retrospective study included 47 patients with obstructive left-sided PVT and 32 controls in whom PVT was excluded with comprehensive transthoracic and transesophageal echocardiography (TEE). The patient group included 11 aortic, 27 mitral, and 9 aortic and mitral valve PVT patients and the control group included 2 aortic, 25 mitral, and 5 aortic and mitral valve patients. Laboratory analysis including plasma D-dimer levels was performed at the time of admission in all patients. The baseline characteristics were similar between the two groups. The plasma D-dimer levels were significantly higher in patients with obstructive PVT compared with controls [680 (110-3590) vs. 310 (80-380) μg/l; P < 0.001]. By multivariate logistic regression analysis high D-dimer level, low-INR value on admission, high NYHA functional class and recent history of cerebrovascular accident (CVA), and transient ischemic attack (TIA) were the independent predictors of obstructive PVT. A plasma D-dimer level of greater than 365 μg/l predicted the presence of PVT with a sensitivity of 81% and a specificity of 69% (AUC= 0.781, P < 0.001). Plasma D-dimer levels were significantly higher in patients with a recent history of CVA/TIA [2140 (470-2980) vs. 590 (380-830) μg/l; P = 0.021]. In addition to the so-called indicators of PVT including subtherapeutic anticoagulation, increased D-Dimer levels may strengthen the suspicion of PVT. Moreover, higher plasma D-dimer levels were associated with higher thrombus burden and higher prevalence of recent CVA/TIA.

Background: Prosthetic valve thrombosis (PVT) may impair pulmonary venous flow (PVF) and left atrial appendage (LAA) functions. An investigation was conducted to determine the association between left superior PVF and LAA functions and mitral PVT., Methods: This observational case-control study included 100 consecutive patients (87 females, 13 males; mean age 59 years; range 35-71 years) with mechanical mitral PVT, and 50 age- and gender-matched otherwise healthy controls with normally functioning mitral prostheses. All patients were included after comprehensive transesophageal echocardiography (TEE) examinations for the presence and quantification of PVT, the left atrial diameter, and LAA length. Peak systolic velocity (PSV), velocity-time integral of systolic flow (VTI-s), peak diastolic velocity (PDV), velocity-time integral of diastolic flow (VTI-d), systolic fraction (SFr) of the left upper PVF and the flow of the LAA orifice were each recorded using color-guided pulsed-wave Doppler imaging during TEE., Results: The PSV [30 cm/s (range: 13-77 cm/s) versus 44 cm/s (range: 16-71 cm/s)], respectively (p = 0.002), VTI-s [(2.85 cm (range: 0.5-10.7 cm) versus 5 cm (range: 1.3-12.7 cm)], respectively (p <0.001), VTI-d [(3 cm (range: 0.6-9.7 cm) versus 4.2 cm (range: 1.5-8.3 cm)], respectively (p <0.001), SFr (45.5% (range: 15.66-67.44%) versus 50 % (range: 21.11-82.61%)], respectively (p = 0.008), and LAA orifice velocity [(23 cm/s (range: 11-75 cm/s) versus 34 cm/s (range: 10-112 cm/s)], respectively (p = 0.011) were each significantly lower in patients with PVT compared to controls. The PDV was similar between groups. Patients with obstructive PVT (n = 21) had a lower PDV and a higher VTI-d compared to those with non-obstructive PVT., Conclusions: Mitral mechanical PVT is associated with decreased systolic PVF and LAA function. The presence of obstructive PVT is associated with further limitations of diastolic flow velocity, and a compensatory prolongation of diastolic flow of the left upper pulmonary vein.

Background and Aim of the Study: Protein Z (PZ) is a vitamin K-dependent factor that is synthesized mainly by the liver. It acts as an activator of serpin, the protein Z-dependent inhibitor (ZPI), which inhibits factor Xa. The potential role of alterations in protein Z and/or ZPI levels in the pathogenesis of thrombotic and/or hemorrhagic diseases has been previously investigated, but results have been conflicting. The study aim was to evaluate the role of PZ/ZPI polymorphisms in the development of prosthetic valve thrombosis (PVT)., Methods: This prospective, observational cross-sectional study included 50 consecutive patients with PVT [non-obstructive thrombosis (NOT) in 35 patients; obstructive thrombosis (OT) in 15] and 50 consecutive healthy subjects with normally functioning prostheses. gDNA was extracted from ca. 5 × 106 leukocytes, using the QIAamp DNA Mini Kit (Qiagen), according to the manufacturer's recommendations. For mutational analysis, a minisequencing method was employed. Results of the analyses were compared between the PVT and control groups, and also between the OT and NOT subgroups., Results: The frequency of A allele (mutant type) of PZG79A was equal in all PVT patients and in controls. With regards to PZ-A13G polymorphisms, frequency of the mutant G allele was 22% in PVT patients and 19% in controls. Serpina-R67X polymorphism was observed in 8% of PVT patients and 6% of controls. Normal variant CC was present in 47 controls (94%), whereas a heterozygotic mutation (CT) was detected in four PVT patients (8%). Frequency of the ZPI-R67X mutation was significantly higher in patients with OT than in those with NOT (p = 0.041)., Conclusions: The present study was the first to evaluate the potential impact of PZ (PZ-A13G, PZG79A) and ZPI (R-67X, W303X) polymorphisms in the development of PVT. Based on the results of this small observational case-control study, PZ/ZPI polymorphisms do not appear to play an active role in the development of PVT. Hence, further extensive studies are necessary.

Background: The outcomes of thrombolytic therapy (TT) in elderly patients with prosthetic valve thrombosis (PVT) have not been evaluated previously. We investigated the outcomes of low-dose and slow infusion TT strategies in elderly patients with PVT., Methods: Twenty-seven (19 female) patients aged ≥65 years (median: 70 years, range: 65-82 years) were treated with repeated TT agents for PVT. The TT regimens included 24-hour infusion of 1.5 million units of streptokinase in 2 patients, 6-hour infusion of 25 mg recombinant tissue plasminogen activator (t-PA) in 12 patients, and 25-hour infusion of 25 mg t-PA in 13 patients. Treatment success and adverse event rates were assessed., Results: The initial and cumulative success rates were 40.7% and 85.2%, respectively. Adverse events occurred in 6 (22.2%) patients including 4 (14.8%) major (1 death, 1 rethrombosis, and 2 failed TT) and 2 (7.4%) minor (1 transient ischemic attack and 1 access site hematoma) events. Higher thrombus burden (thrombus area ≥1.1 cm 2 by receiver operating characteristics analysis, sensitivity: 83.3%, specificity: 85%, area under the curve: 0.86, P = .008) and New York Heart Association class (0% vs 15.4% vs 25% vs 100% for classes I-IV, respectively, P = .02) predicted adverse events. By multiple variable analysis, thrombus area was the only independent predictor of adverse events (odds ratio: 13.8, 95% confidence interval: 1.02-185, P = .04)., Conclusion: Slow infusion of low doses of TT agents (mostly t-PA) with repetition is successful and safe in elderly patients with PVT. However, excessive thrombus burden may predict adverse events.

Prosthetic valve thrombosis is one of the major causes of primary valve failure, which can be life-threatening. Multimodality imaging is necessary for determination of leaflet immobilization, cause of underlying pathology (thrombus versus pannus or both), and whether thrombolytic therapy attempt in the patient would be successful or surgery is needed. Current guidelines for the management of prosthetic valve thrombosis lack definitive class I recommendations due to lack of randomized controlled trials, and usually leave the choice of treatment to the clinician's experience. In this review, we aimed to summarize the pathogenesis, diagnosis, and management of mechanical prosthetic valve thrombosis.

Objective: The non-O alleles of the ABO genotype have been associated with an increased risk of thrombosis. We aimed to assess the association between blood group status and prosthetic valve thrombosis., Methods: The association between AB0 blood group status and prosthetic valve thrombosis was assessed in this retrospective study. Transesophageal echocardiography was performed in 149 patients with a diagnosis of prosthetic valve thrombosis and in 192 control subjects., Results: Non-0 blood group type (p<0.001), presence of NYHA class III-IV status (p<0.001), and central nervous system (p<0.001) and non-central nervous system (p<0.001) emboli were significantly more prevalent in prosthetic valve thrombosis patients than in the control subjects. The incidence of ineffective anticoagulation was higher in patients with prosthetic valve thrombosis than in controls (p<0.001), as was the presence of moderate to severe left atrial spontaneous echo contrast (p<0.001). The non-0 blood prosthetic valve thrombosis subgroup had a higher incidence of obstructive thrombi and central nervous system thrombotic events than having 0 blood prosthetic valve thrombosis subgroup. Non-0 blood group, ineffective anticoagulation, left atrial spontaneous echo contrast, and a poor NYHA functional capacity were identified to be the predictors of prosthetic valve thrombosis., Conclusion: Our data demonstrate that patients with non-0 compared with 0 blood groups have higher incidence of prosthetic valve thrombosis and central nervous system embolism and similar rates of non-central nervous system embolism at presentation compared with 0 blood group type. Thus, non-O blood group may be a risk factor that may be prone to the development of prosthetic valve thrombosis in patients with prosthetic heart valves.

Background: Thrombolysis is an effective treatment strategy for prosthetic valve thrombosis (PVT). Recombinant tissue-type plasminogen activator (rt-PA) is widely used as a thrombolytic agent. Infusion of rt-PA may trigger the production of anti-tissue plasminogen activator (tPA) antibodies (ATAs). We aimed to evaluate the possible relationship between ATA levels and PVT formation, and the role of baseline ATA levels on outcomes of thrombolytic therapy in patients with PVT., Methods: This prospective, single-center cohort study included 28 patients with PVT undergoing thrombolysis and 31 controls with normal prostheses. Plasma samples were collected from patients with PVT at baseline and at 15th, 30th, 90th, and 180th days after thrombolysis and from controls at baseline only. The ATA levels were assessed in human plasma by an enzyme-linked immunosorbent assay., Results: Baseline ATA-immunoglobulin (Ig) G and IgM were significantly higher in patients with PVT than in controls. The levels of IgM and IgG peaked at 15th and 30th days after rt-PA infusion, respectively. Subtherapeutic international normalized ratio and baseline ATA-IgM were independent predictors of PVT. Thrombolysis failed in 6 patients (21%) in whom baseline IgM levels were significantly higher than successfully lysed patients. Rethrombosis occurred in 9 patients (32%) in whom baseline IgG levels were significantly higher than those without rethrombosis. There was a moderate positive correlation between baseline and 15th-day IgM levels and the dose of rt-PA needed for successful lysis., Conclusion: The ATA levels tended to be higher in patients with PVT at the time of initial diagnosis compared to controls without PVT. In addition, such patients with PVT and high ATA levels may be at high risk for failed thrombolysis or rethrombosis., (© The Author(s) 2015.)

Background and Aim of the Study: Paravalvular leakage (PVL) remains an unavoidable complication of heart valve surgery and in its severe forms may lead to heart failure and hemolysis. The study aim was to evaluate the echocardiographic, clinical, surgical and laboratory characteristics of patients with aortic PVL., Methods: A total of 77 aortic PVL patients underwent transthoracic and transesophageal echocardiography examinations. Clinical, echocardiographical and surgical findings were also recorded., Results: Among the 77 patients, 21 (27.3%) had mild, 33 (42.8%) had moderate and 23 (29.9%) had severe aortic PVL. Seventeen patients (22.1%) had moderate-to-severe hemolysis and had a higher incidence of multiple PVL compared to those with no or mild hemolysis. Moderate- to-severe PVL was more frequent between the non-coronary and the left coronary sinus annuli, especially adjacent to the left main coronary artery ostium. Percutaneous closure was performed in five patients. Eleven patients underwent surgical repair, and the localizations of PVL were in accordance with echocardiographic findings., Conclusions: Aortic PVL occurs more frequently between the non-coronary sinus and the left coronary sinus annuli, which may be associated with multiple factors. Difficulties in seating the prosthesis due to the steep angulation of the commissure and annulus, the avoidance of deep sutures, and focal annular calcification may make this region prone to injury and leakage.

Prosthetic valve thrombosis is a severe complication, which usually occurs in inadequately anticoagulated patients. Mechanical valve thrombosis is more common than bioprosthetic valve thrombosis (BVT). Oral contraceptive drugs are associated with increased risk of thromboembolism in women. The possible association between oral contraceptive drug use and BVT has never been reported before. We present a case of obstructive BVT occurring after the use of an oral contraceptive drug and successful management with ultra-slow thrombolytic therapy.

Background: Prosthetic valve dysfunction due to pannus formation is a rare but serious complication. Currently, limited data are available concerning the pathogenesis and immunohistochemical properties of pannus. The study aim was to investigate the morphological, histopathological and immunohistochemical characteristics of pannus formation in patients with prosthetic valve dysfunction., Methods: A total of 35 patients (10 males, 25 females; mean age 44 ± 16 years) who had undergone re-do valve surgery due to prosthetic valve obstruction was enrolled in the study. Immunohistochemical studies were aimed at evaluating the expression of alphasmooth muscle actin (α-SMA) and desmin in myofibroblasts and smooth muscle cells; epithelial membrane antigen (EMA) in epithelial cells; and CD34, Factor VIII and vascular endothelial growth factor (VEGF) in endothelial cells. Matrix metalloproteinases (MMPs) -2 and -9, and transforming growth factor-beta (TGF-β) were used to demonstrate cytokine release from macrophages, leukocytes, fibroblasts and myofibroblasts., Results: Pannus appeared as a tough and thick tissue hyperplasia which began from outside the suture ring in the periannular region and extended to the inflow and outflow surfaces of the prosthetic valves. Histopathological analysis showed the pannus tissue to consist of chronic inflammatory cells (lymphocytes, plasma cells, macrophages and foreign body giant cells), spindle cells such as myofibroblasts, capillary blood vessels and endothelial cells laying down the lumens. Calcification was present in the pannus tissue of 19 explanted prostheses. Immunohistochemical studies revealed positive α-SMA expression in all patients, whereas 60.5% of patients were positive for desmin, 50% for EMA, 42.1% for VEGF, 39.5% for TBF-β, 42.1% for MMP-2, 86.8% for CD34, and 97.4% for Factor VIII. MMP-9 was negative in all patients., Conclusions: Pannus tissue appears to be formed as the result of a neointimal response in periannular regions of prosthetic valves that consist of periannular tissue migration, myofibroblast and extracellular matrix proliferation with vascular components. It is a chronic active process in which mediators such as TGF-β, VEGF and MMP-2 play roles in both matrix formation and degradation.

Background: Distinguishing pannus and thrombus in patients with prosthetic valve dysfunction is essential for the selection of proper treatment. We have investigated the utility of 64-slice multidetector computed tomography (MDCT) in distinguishing between pannus and thrombus, the latter amenable to thrombolysis., Methods and Results: Sixty-two (23 men, mean age 44±14 years) patients with suspected mechanical prosthetic valve dysfunction assessed by transesophageal echocardiography were included in this prospective observational trial. Subsequently, MDCT was performed before any treatment was started. Periprosthetic masses were detected by MDCT in 46 patients, and their attenuation values were measured as Hounsfield Units (HU). Patients underwent thrombolysis unless contraindicated, and those with a contraindication or failed thrombolysis underwent surgery. A mass which was completely lysed or surgically detected as a clot was classified as thrombus, whereas a mass which was surgically detected as tissue overgrowth was classified as pannus. A definitive diagnosis could be achieved in 37 patients with 39 MDCT masses (22 thrombus and 17 pannus). The mean attenuation value of 22 thrombotic masses was significantly lower than that in 17 pannus (87±59 versus 322±122; P<0.001). Area under the receiver operating characteristic curve was 0.96 (95% confidence interval: 0.91-0.99; P<0.001), and a cutoff point of HU≥145 provided high sensitivity (87.5%) and specificity (95.5%) in discriminating pannus from thrombus. Complete lysis was more common for masses with HU<90 compared with those with HU 90 to 145 (100% versus 42.1%; P=0.007)., Conclusions: Sixty-four slice MDCT is helpful in identifying masses amenable to thrombolysis in patients with prosthetic valve dysfunction. A high (HU≥145) attenuation suggests pannus overgrowth, whereas a lower value is associated with thrombus formation. A higher attenuation (HU>90) is associated with reduced lysis rates., (© 2015 American Heart Association, Inc.)

Background and Aim of the Study: Prosthetic valve dysfunction (PVD) due to pannus formation is considered to occur due to a bioreaction to prosthetic material. The p53 gene plays a critical role in apoptosis and cell proliferation. p53 Arg72Pro polymorphism has been found to be associated with coronary stent restenosis, but has not yet been studied in prosthetic heart valve dysfunction. The study aim was to evaluate the association between pannus-derived PVD and p53 G72C(Arg72Pro) polymorphism., Methods: This single-center, prospective study included 25 patients (20 females, five males; mean age 45.6 +/- 12.5 years; group 1) who underwent redo valve surgery due to PVD, and 49 age- and gender-matched control patients (44 females, five males; mean age 47.3 +/- 12.2 years; group 2) with normofunctional prostheses. The prostheses were examined using transthoracic and transesophageal echocardiography. Analyses of p53 G72C(Arg72Pro) polymorphism were performed using Roche LightCyler 2.0 Real-time polymerase chain reaction., Results: The most common location of replaced valves was the mitral position in both groups (88% and 89.8%, respectively). In group 1, normal alleles (GG) were observed in 12 patients (48%), while one patient (4%) showed a homozygous mutation (GC) and 12 patients (48%) showed a heterozygous mutation (CC). In group 2, 21 patients (42.9%) had normal alleles (GG), while four (8.2%) had a homozygous mutation (CC) and 24 (48.9%) had a heterozygous mutation (GC). No significant difference was observed between the groups with regards to p53 Arg72Pro polymorphism (p = 0.769)., Conclusion: In patients with prosthetic valves, the underlying mechanism behind pannus formation is unrelated to p53 Arg72Pro polymorphism.

Background: Low-dose (25mg), slow infusion (6hours) of tissue-type plasminogen activator (t-PA) with repetition as needed has been shown to provide effective and safer thrombolysis in patients with prosthetic valve thrombosis (PVT). Further prolonging the infusion time may be rational with regard to reducing complication rates without reducing success rates. We aimed to investigate the efficacy and safety of ultraslow (25hours) infusion of low-dose (25mg) alteplase (t-PA) for PVT., Methods and Results: Transesophageal echocardiography-guided thrombolytic therapy (TT) was administered to 114 patients with PVT in 120 different episodes between 2009 and 2013 in a single center. Prosthetic valve thrombosis was obstructive in 77 (64.2%) and nonobstructive in 43 (35.8%) episodes. Ultraslow infusion (25hours) of low-dose (25mg) t-PA, as the TT regimen, was used in all patients admitted with PVT. The end points were thrombolytic success, mortality, and complication rates. The overall success rate of TT was 90% (95% CI 0.85-0.95). The univariate predictors of an unsuccessful result were higher New York Heart Association (NYHA) class, thrombus cross-sectional area, duration of suboptimal anticoagulation, lower baseline valve area, and presence of atrial fibrillation. The NYHA class was the only independent predictor of TT failure by multiple variable analysis. The overall complication rate was 6.7% (3.3% nonfatal major, 2.5% minor, and 0.8% death). The predictors of complications were presence of atrial fibrillation, higher NYHA class, and thrombus area., Conclusion: Ultraslow (25hours) infusion of low-dose (25mg) t-PA without bolus appears to be associated with quite low nonfatal complications and mortality for PVT patients without loss of effectiveness, except for those with NYHA class IV., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Coronary thromboembolism is a rare cause of acute coronary syndromes (ACS). The information regarding ACS in patients with prosthetic heart valves is scarce and based mainly on case reports. Although plaque rupture is the most common cause of acute myocardial infarction, coronary embolism (CE) is not a rare cause of acute myocardial infarction. There is no consensus regarding the treatment in such a situation. We present three cases of prosthetic valve thrombosis complicated with CE causing non-ST elevation ACS, who were successfully treated with thrombolytic therapy (TT). We administered low-dose (25 mg), slow-infusion (6 hours) tissue plasminogen activator (t-PA), which was shown to be safe and effective in our group in a large study. The patients benefited from TT with respect to the coronary flow, as shown by the lysis of thrombi in all three patients on coronary angiogram.

Prosthetic valve thrombosis (PVT) is a life-threatening complication. Neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) have been studied as inflammatory biomarkers in atherosclerosis, but data regarding valvular disease are lacking. The study population included patients with mitral PVT (n = 152) versus control subjects (n = 164) with functional mitral prosthesis. Transesophageal echocardiography was performed to diagnose PVT. NLR and PLR were calculated using complete blood count. C-reactive protein (CRP) levels were also analyzed. Neutrophil and platelet levels did not differ between the groups (4.9 ± 2.0 vs 4.7 ± 1.5, p = 0.84 and 254.8 ± 89.7 vs 241.5 ± 62.8 p = 0.36, respectively), but lymphocyte levels were significantly lower in patients with PVT than the controls (1.8 ± 0.7 vs 2.2 ± 0.6, p <0.001). NLR, PLR, and CRP levels were significantly higher in patients with PVT than in controls (3.2 ± 2.1 vs 2.2 ± 0.8, p <0.001; 163 ± 77.5 vs 114.9 ± 37.3, p <0.001; and 1.97 ± 3.02 vs 1.02 ± 1.22, p = 0.01, respectively). A positive correlation was observed between NLR and PLR (r = 528, p <0.001). NLR level of >2.23, measured on admission, yielded an area under the curve value of 0.659 (95% confidence interval 0.582 to 0.736, sensitivity 66%, specificity 60%, p <0.001) and PLR level of >117.78 yielded an area under the curve value of 0.707 (95% confidence interval 0.636 to 0.777, sensitivity 70%, specificity 58%, p <0.001). Multivariate analysis showed that increased PLR and inadequate anticoagulation were independent predictors of thrombosis in patients with PVT. In conclusion, patients with PVT had increased NLR, PLR, and CRP levels compared with subjects with normofunctional prosthesis, and increased PLR was an independent predictor of mitral PVT., (Copyright © 2014 Elsevier Inc. All rights reserved.)