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 Table of Contents  
Year : 2016  |  Volume : 2  |  Issue : 2  |  Page : 103-109

Streptokinase versus recombinant tissue-type plasminogen activator for thrombolysis of mechanical prosthetic heart valve thrombosis

Department of Cardiology, All Institute of Medical Sciences, New Delhi, India

Date of Web Publication7-Oct-2016

Correspondence Address:
Nilkanth Chandrakant Patil
Senior Resident, Department of Cardiology, All India Institute of Medical Sciences, New Delhi-110029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2395-5414.191520

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Aims and Objectives: This study was designed to compare streptokinase (STK) versus recombinant tissue-type plasminogen activator (rt-PA) for thrombolysis in patients with prosthetic heart valve thrombosis (PHVT). Background: Optimal management of PHVT remains controversial. Thrombolytic therapy is a reasonable alternative to surgery. Numerous thrombolytic protocols with STK, urokinase, and rt-PA have been used over the past 40 years. So far there is a lack of consensus on the ideal thrombolytic agent for PHVT. There are no major studies comparing efficacy of STK versus rt-PA. Methods and Results: Sixty patients who underwent thrombolysis for PHVT over 1 year were studied. Forty-eight patients were thrombolysed with STK, whereas 12 patients received rt-PA. Overall 68.33% (41/60) patients showed complete response (CR), whereas 85% (51/60) showed some improvement in hemodynamics, with no significant difference in efficacy according to age, sex, duration from surgery, New York Heart Association Class III–IV, presence of atrial fibrillation, type of valve, or history of stroke. Overall 10% patients developed major complications with mortality of 5%. CR to thrombolytic therapy was numerically better with STK (72.9% vs. 50%; P = 0.12) and mortality was significantly higher in rt-PA (16.6% vs. 2%, P = 0.038). Mean duration of successful thrombolysis was significantly longer with STK as compared to rt-PA (22.96 ± 19.2 vs. 3 h). Conclusion: STK use as compared to rt-PA was associated with numerically more successful thrombolysis and significant lower mortality, hence may be optimal for elective thrombolysis.

Keywords: Prosthetic heart valve thrombosis, recombinant tissue-type plasminogen activator, streptokinase, thrombolysis

How to cite this article:
Patil NC, Doshi S, Singh S, Karthikeyan G, Bahl VK. Streptokinase versus recombinant tissue-type plasminogen activator for thrombolysis of mechanical prosthetic heart valve thrombosis. J Pract Cardiovasc Sci 2016;2:103-9

How to cite this URL:
Patil NC, Doshi S, Singh S, Karthikeyan G, Bahl VK. Streptokinase versus recombinant tissue-type plasminogen activator for thrombolysis of mechanical prosthetic heart valve thrombosis. J Pract Cardiovasc Sci [serial online] 2016 [cited 2023 Feb 7];2:103-9. Available from: https://www.j-pcs.org/text.asp?2016/2/2/103/191520

  Introduction Top

Prosthetic heart valve thrombosis (PHVT) is a rare but potentially life-threatening complication of heart valve replacement. The incidence of thromboembolic complications in patients of prosthetic valves has been estimated to range from 0.03 to 4.3% per patient-year in developed countries.[1] In India, it is 6.1% within 6 months of valve replacement and 10% over 1 year.[2],[3]

Although surgery is usually favored over thrombolytic therapy, optimal management of PHVT remains controversial.[4],[5] Initially, thrombolytic therapy was proposed by many authors as the first line of therapy for PHVT, but most of the recent guidelines favor surgery, with thrombolytic therapy reserved for patients with low thrombus burden and to those with highest surgical risk.[1],[4],[5],[6] In India, we still follow thrombolytic therapy as the first treatment of choice in all patients irrespective of functional class and transesophageal echocardiographic (TEE) findings, with surgery reserved for patients with contraindications to thrombolysis and in patients with failed thrombolysis.[2],[7] This is because of high surgical burden of valve surgeries and high cost of repeat surgery.[8]

Drugs used for thrombolytic therapy include streptokinase (STK), recombinant tissue-type plasminogen activator (rt-PA), and urokinase (UK). UK is less efficacious and hence not much used nowadays. rt-PA is preferred over STK in other indication of thrombolysis such as myocardial infarction and stroke; however, benefit of rt-PA over STK in PHVT is not proven.[9],[10],[11] Results reported with rt-PA in PHVT have been varying ranging from 40 to 100% in small case series.[9],[11],[12] There are no studies directly comparing rt-PA versus STK for PHVT. Hence, we conducted this study to compare the efficacy and adverse effects of STK as compared to rt-PA when used for thrombolysis in patients with left-sided PHVT.

  Methods Top

Consecutive patients diagnosed with PHVT of left-sided valve(s) who underwent thrombolysis, at cardiac care unit of our institution over a 1-year period from January 2011 to December 2011, were included in the study. PHVT was diagnosed on the basis of cinefluoroscopic and transthoracic echocardiographic findings. Patients with PHVT who were <12 years and those with contraindication to thrombolytic therapy were excluded from the analysis. Contraindications to thrombolytic therapy included any previous intracranial hemorrhage, major bleeding within past 2 weeks, ischemic stroke within the last 3 months, presence of a left atrial thrombus on transthoracic echocardiography, and pregnancy. The study protocol was approved by the Institute's Ethics Committee.

Definitions used in study

PHVT: New onset of hypomobile or immobile valve leaflets on cinefluoroscopy,[13],[14] with or without elevated transvalvular gradients on Doppler echocardiography.

Success of thrombolytic therapy is defined as:

  • Complete response (CR): Clinical and hemodynamic improvement with normal leaflet mobility on fluoroscopy and normalization of valve gradients on echocardiography (for mitral valve - mean diastolic gradient <6 mm Hg and end-diastolic gradient <2 mm Hg and aortic valve - peak gradient <30 mm Hg 2) in the absence of major complications including major thromboembolic event/death
  • Partial response (PR): Clinical and hemodynamic improvement with incomplete recovery of leaflet mobility on fluoroscopy and decrease in valve gradients (improvement in transvalvular gradients >50% from baseline [2]) on echocardiography in the absence of major complications including major thromboembolic event/death
  • Failure: No clinical improvement or associated with death or major complications.

Major complications were defined as:

  • Death: Death during thrombolysis or within 24 h of thrombolysis
  • Major bleeding: Bleeding that was intracranial, required transfusion, or led to surgical exploration
  • Major thromboembolic event is defined as cerebral thromboembolic event resulting in focal neurological deficit lasting >24 h and confirmed by brain imaging, or a peripheral embolic event confirmed by Doppler or other imaging modality requiring surgical intervention.

Outcomes studied

Primary outcome

The primary outcome was to study CR following thrombolytic therapy with rt-PA compared to STK.

Secondary outcome

  • Overall efficacy and complication of thrombolytic therapy
  • Efficacy of thrombolysis as defined by CR, PR, or any hemodynamic improvement (CR + PR) with rt-PA as compared to STK
  • Comparative mortality in two groups.

Study intervention

The choice of thrombolytic therapy was based on physician preference and availability of the drug at that time.

In all cases, treatment was selected in agreement with the surgical team. Those patients receiving STK received 250,000 units bolus over 30 min followed by 100,000 units/h. rt-PA was used as 100 mg intravenous infusion over 3 h. Patients were monitored continuously. Cinefluoroscopy and Doppler echocardiography were done at the end of 30 min, 3 h, 6 h, and then every 6 h or after any change in clinical status. STK infusion was stopped after successful thrombolysis in patients with CR, whereas it was continued for up to 72–96 h in patients with partial/no response at the discretion of the treating physician.

Statistical analyses

Analyses were performed with SPSS version 17 (SPSS Inc., Chicago, IL, USA). After verification of the normality of distribution of the continuous variables, means and standard deviations are calculated. Student's t-test (two-tailed, independent) was used to find the significance of study parameters on continuous scale between two groups (intergroup analysis) on metric parameters. Chi-square was used to find the significance of study parameters on categorical scale between two groups. P < 0.05 was considered statistically significant.

  Results Top

Between January 2011 and December 2011, we identified 69 patients with left-sided PHVT who underwent thrombolysis. Out of which sixty patients, whose complete data could be retrieved, were included in final analysis.

Baseline characteristics of sixty patients are as summarized in [Table 1]. The mean age was 30.25 ± 9.1 years (range - 14–55 years). The mean time between prosthetic heart valve replacement and the thrombotic episode was 4.9 ± 3.9 years (range - 2, months - 16 years) with most patients (40%) presenting within 1–2 years of surgery. Among PHVT, mitral valve was thrombosed in 27 patients, aortic valve in 29, and four patients had both valves affected. Forty-nine (81.66%) patients had the first episode of PHVT, whereas nine patients (15%) had second and one patient each had third and fourth episode of PHVT.
Table 1: Baseline characteristic of all patients

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Clinical characteristics

The main clinical features among symptomatic patients with PHVT at the time of presentation were recent onset worsening of dyspnea, decreased valve click, and congestive heart failure. A significant number of patients 12 (20%) were asymptomatic and were detected to be having PHVT by routine follow-up cinefluoroscopy and echocardiogram.

Among patients who were symptomatic, two-third of the patients (32/48) had new or worsening symptoms within last 2 weeks. Atrial fibrillation (AF) was present at diagnosis in one-third (33.33%) of the patients. A history of previous stroke was present in 11% of patients. STK was used in 48 (80%) patients, whereas rt-PA was used in 12 (20%) patients.

Overall efficacy of thrombolysis

Efficacy of thrombolytic therapy was evaluated from the clinical data, Doppler echocardiographic findings, and cinefluoroscopy. Definition of CR, PR, and failed thrombolytic therapy is as mentioned before. Overall 68.3% (41 patients) showed CR, 85% (51 patients) showed some improvement in hemodynamics (CR + PR), whereas 15% (9) completely failed to respond [Figure 1].
Figure 1: Overall outcome of thrombolysis. CR = complete response; CR + PR = complete plus partial response.

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There was no significant difference in efficacy according to the baseline characteristics; however, there was a trend toward worse outcomes in terms of CR in patients with New York Heart Association (NYHA) Class III–IV as compared to NYHA I–II (77.1% vs. 56%; P = 0.083), and in patients with AF (54% vs. 76.3%; P = 0.081) [Figure 2]. Thrombolytic therapy was equally effective in first and recurrent episodes of PHVT.
Figure 2: Success according to rhythm and functional class. AF = atrial fibrillation; NSR = normal sinus rhythm.

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Comparison of streptokinase versus recombinant tissue-type plasminogen activator for thrombolysis

There was no significant difference in the baseline characteristic in the two groups [Table 2]. However, there were more patients with second or recurrent episodes in rt-PA group. CR to thrombolytic therapy was better with STK as compared to rt-PA (72.9% vs. 50%; P = 0.12); however, it did not reach the statistical significance. Hemodynamic response (CR + PR) was also better in STK group (87.5% vs. 75%) [Figure 3]. Mortality was significantly higher in rt-PA group as compared to STK group (16.6% vs. 2%, P = 0.038).
Table 2: Baseline characteristics of patient's thrombolysed with streptokinase versus recombinant tissue-type plasminogen activator

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Figure 3: Success of thrombolytic therapy in patient's thrombolysed with streptokinase versus recombinant tissue-type plasminogen activators. CR = complete response; CR + PR = complete plus partial response; STK = streptokinase; rt-PA = recombinant tissue-type plasminogen activators.

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Rapidity of clinical response

All the patients who showed CR with rt-PA showed a response within 6 h, whereas with STK, mean time for CR was 22.96 ± 19.2 h, significantly longer than that of patients' thrombolysed with rt-PA.

Complications of thrombolysis

Overall 10% (6) patients developed major complications. Four patients developed significant intracranial bleeding (2 each in STK and rt-PA group) and 2 patients developed major cerebroembolic event (both in STK group).

In STK group, of the patients with major cerebroembolic event, one patient developed right-sided hemiparesis within 2 h of thrombolysis (however with successful opening of his valve); another developed bilateral middle cerebral artery infarction and died after nearly 1 month of supportive treatment (her Doppler echocardiography had shown significant fall in gradient with partial normalization of leaflet movements on cinefluoroscopy). Of the two patients with intracranial bleed, one had cerebellar bleed, and another had frontal lobe bleed, both improved with conservative management and underwent valve surgery at a later date.

In rt-PA group, two patients developed intracranial bleed, both expired despite extensive supportive treatment.

There was no significant difference in total complications in two treatment groups (8.3% in STK vs. 16.6% in rt-PA, P = 0.5); however, mortality was significantly higher in rt-PA group (2% vs. 16.6%, P = 0.038).

  Discussion Top

Overall outcome of thrombolytic therapy

The overall success rate of thrombolysis was 68.33% (CR) with 85% of patients showing some hemodynamic improvement (CR + PR). Major complications were seen in 10% of patients with mortality rate of 5%. The overall success rate and complication in our study are in agreement with the previous large series of thrombolysis in patients of PHVT by Roudaut et al.[10] (70.9%), Gupta et al.[7] from our center (73%), Nagy et al.[15] (73%), and many other case series.

Our study population is different since we use thrombolysis as the first treatment of choice irrespective of their TEE findings. Despite this fact, there is no attrition in results, and complications are same as reported in developed countries.

All three deaths in our study were in female patients. Female sex had emerged as a significant predictor of hemorrhagic complications in a previous study from our center.[7] Hence, their hypothesis that the dose of thrombolytic used might be high for the Indian women should be given some thought, and further studies should address this issue. In our study, 12 (20%) patients were asymptomatic and were detected during routine follow-up which underscores the importance of careful vigilance during follow-up of these patients by cinefluoroscopy and Doppler echocardiography.

Comparison of streptokinase versus recombinant tissue-type plasminogen activator

Rt-PA is routinely used in patients with acute ST-elevation myocardial infarction (STEMI) and in indicated patients of ischemic stroke and has been found superior to STK.[16] This superiority of rt-PA may not be applicable to patients with PHVT. The pathophysiology of STEMI and stroke is different from PHVT. They have a small thrombus burden and require a rapidly acting thrombolytic agent because of acuity of the illness as compared to the patients of PHVT where thrombus burden is high, and a slow and controlled lysis may be more desirable.

In the present study, rt-PA was not found to be superior to STK; in fact, CR or total hemodynamic response was numerically lower when rt-PA was used. Mortality was significantly higher in rt-PA group implying that complications with rt-PA are more likely to be fatal.

A recent randomized controlled trial from our center comparing accelerated STK versus conventional STK found no advantage of accelerated regimen in terms of efficacy and a concerning increase in bleeding and embolization.[2] A similar analogy can be applied to rt-PA, which acts in an accelerated fashion and the same mechanistic can be applied to explain the lack of benefit and more complications and deaths in rt-PA group.

Mechanism for increased mortality with recombinant tissue-type plasminogen activator

When STK is used its total dose is given over a long period as a continuous infusion; hence if bleeding/complication(s) occurs, it can be stopped in between and further expansion of bleed or hemorrhagic transformation of ischemic stroke can be limited. This is not the case with rt-PA where the entire thrombolytic dose is rapidly given over a short period of time.

In rt-PA group, all patients ended up getting the entire scheduled dose of thrombolytic, whereas STK is discontinued if the valve is opened in less than the scheduled duration of thrombolytic therapy, hence overall total dose received will be less than maximum. This might be one of the explanations for increased life-threatening bleeds in rt-PA group.

Dose of rt-PA used was 100 mg over 3 h which is as recommended by the earlier studies, irrespective of body weight. This might not have been the case with Indian patients who have a lower body weight and might have received a higher dose than required.

This high dose along with the rapidity of action of rt-PA might be responsible for higher mortality seen in patients with rt-PA.

Rapidity of action

When analyzed for rapidity of action, all patients who showed a response to rt-PA improved within 6 h, indicating a rapid action which can have significant clinical implications. A patient who presents in NYHA Class IV or in shock will not give much time as required for thrombolysis with STK, and delay in valve opening might further worsen an already compromised patient. Such patients might benefit from thrombolysis by rt-PA.

Previous studies of recombinant tissue-type plasminogen activator

[Table 3] gives a detailed overview of major studies using rt-PA in PHVT. Vitale et al.[17] reported a first major series of eight PHVT patients thrombolysed with rt-PA in 1994 and showed complete clinical response in all eight patients. Later studies could not obtain the same success with rt-PA with widely varying results from 43% to 100% [Table 3].[9],[10],[12],[18],[19],[20],[21]
Table 3: Previous major case series of result of thrombolysis with recombinant tissue-type plasminogen activator in prosthetic heart valve thrombosis

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All these studies have recruited patients over a long duration, from 1978 to 2000, a period over which treatment strategies (more patients received thrombolysis in earlier period, whereas only patients with low thrombus burden or low risk received thrombolysis in later time period), patient monitoring (more frequent use of TEE and more frequent use of fluoroscopy and echocardiographic monitoring in later study period), supportive care (earlier brain imaging and better critical care), and the type of valves used (less bulky valves used recently) has undergone significant changes. Hence, the patient group is heterogeneous and not comparable to each other or to the current management. Besides, there are no direct comparative studies of STK and rt-PA.

Our results with rt-PA were closer to that of Roudaut et al.[10] and Shapira et al.[9] which represent the largest of the group. One major series recently reported the results of thrombolysis with rt-PA in 13 patients, thrombolysed over 20 year period (1988–2008). They showed initial complete resolution after a single administration of rt-PA in 61% of patients and a significant clinical improvement in 92% with rt-PA.[12] However, the patients included were over a long duration, hence thrombolysed in a different era. They did not compare results with STK, and three out of 13 cases thrombolysed were tricuspid valve thrombosis where the success with thrombolysis is known to be good.

In our study, all patients analyzed were treated within the same time period, and thrombolysis, unless contraindicated, was used in all patients as first line therapy, hence represent a more homogeneous patient population for comparison of different treatment strategies for thrombolysis.

  Conclusion Top

This study has important implications for developing countries where the prevalence of rheumatic disease is high, valve surgeries form a major bulk of open heart surgeries,[8] and incidence of PHVT is higher. In our institution and in many other developing countries, thrombolysis is still the treatment of choices because of its ease of availability and the limitations with surgery (long waiting period and higher cost).[2],[7] Hence, though surgery has become a norm in developed countries, our quest for a better thrombolytic will continue.

Important implications of our study for thrombolysis for PHVT are:

  • Thrombolysis is an effective first-line therapy with acceptable complications
  • In elective thrombolysis for PHVT, STK may be preferred over rt-PA because of its ease of availability, low cost, and probably better efficacy and lower mortality
  • rt-PA has a more rapid clot lysis and hence may be used in critically ill patients
  • The recommended dose of rt-PA of 100 mg over 3 h (irrespective of body weight) might not be correct for the Indian patients, and a weight-based regimen should be studied.

Use of rt-PA in a weight-based regimen along with prolonged low dose continuous infusion (as used by Munclinger et al.[20]) might have slow and controlled lysis and better efficacy than STK without increasing complications. Hence, we suggest that a randomized controlled trial of slow and continuous infusion of rt-PA versus STK.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Lengyel M, Fuster V, Keltai M, Roudaut R, Schulte HD, Seward JB, et al. Guidelines for management of left-sided prosthetic valve thrombosis: A role for thrombolytic therapy. Consensus conference on prosthetic valve thrombosis. J Am Coll Cardiol 1997;30:1521-6.  Back to cited text no. 1
Karthikeyan G, Math RS, Mathew N, Shankar B, Kalaivani M, Singh S, et al. Accelerated infusion of streptokinase for the treatment of left-sided prosthetic valve thrombosis: A randomized controlled trial. Circulation 2009;120:1108-14.  Back to cited text no. 2
Roudaut R, Serri K, Lafitte S. Thrombosis of prosthetic heart valves: Diagnosis and therapeutic considerations. Heart 2007;93:137-42.  Back to cited text no. 3
Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH; American College of Chest Physicians. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141 2 Suppl: e576S-600S.  Back to cited text no. 4
Lengyel M, Horstkotte D, Völler H, Mistiaen WP; Working Group Infection, Thrombosis, Embolism and Bleeding of the Society for Heart Valve Disease. Recommendations for the management of prosthetic valve thrombosis. J Heart Valve Dis 2005;14:567-75.  Back to cited text no. 5
Bonow RO, Carabello B, de Leon AC Jr., Edmunds LH Jr., Fedderly BJ, Freed MD, et al. Guidelines for the management of patients with valvular heart disease: Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on management of patients with valvular heart disease). Circulation 1998;98:1949-84.  Back to cited text no. 6
Gupta D, Kothari SS, Bahl VK, Goswami KC, Talwar KK, Manchanda SC, et al. Thrombolytic therapy for prosthetic valve thrombosis: Short- and long-term results. Am Heart J 2000;140:906-16.  Back to cited text no. 7
Chaturvedi V, Talwar S, Airan B, Bhargava B. Interventional cardiology and cardiac surgery in India. Heart 2008;94:268-74.  Back to cited text no. 8
Shapira Y, Vaturi M, Hasdai D, Battler A, Sagie A. The safety and efficacy of repeated courses of tissue-type plasminogen activator in patients with stuck mitral valves who did not fully respond to the initial thrombolytic course. J Thromb Haemost 2003;1:725-8.  Back to cited text no. 9
Roudaut R, Lafitte S, Roudaut MF, Courtault C, Perron JM, Jaïs C, et al. Fibrinolysis of mechanical prosthetic valve thrombosis: A single-center study of 127 cases. J Am Coll Cardiol 2003;41:653-8.  Back to cited text no. 10
Roudaut R, Lafitte S, Roudaut MF, Reant P, Pillois X, Durrieu-Jaïs C, et al. Management of prosthetic heart valve obstruction: Fibrinolysis versus surgery. Early results and long-term follow-up in a single-centre study of 263 cases. Arch Cardiovasc Dis 2009;102:269-77.  Back to cited text no. 11
Keuleers S, Herijgers P, Herregods MC, Budts W, Dubois C, Meuris B, et al. Comparison of thrombolysis versus surgery as a first line therapy for prosthetic heart valve thrombosis. Am J Cardiol 2011;107:275-9.  Back to cited text no. 12
Montorsi P, De Bernardi F, Muratori M, Cavoretto D, Pepi M. Role of cine-fluoroscopy, transthoracic, and transesophageal echocardiography in patients with suspected prosthetic heart valve thrombosis. Am J Cardiol 2000;85:58-64.  Back to cited text no. 13
Montorsi P, Cavoretto D, Repossini A, Bartorelli AL, Guazzi MD. Valve design characteristics and cine-fluoroscopic appearance of five currently available bileaflet prosthetic heart valves. Am J Card Imaging 1996;10:29-41.  Back to cited text no. 14
Nagy A, Dénes M, Lengyel M. Predictors of the outcome of thrombolytic therapy in prosthetic mitral valve thrombosis: A study of 62 events. J Heart Valve Dis 2009;18:268-75.  Back to cited text no. 15
Adams HP Jr., Adams RJ, Brott T, del Zoppo GJ, Furlan A, Goldstein LB, et al. Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Stroke Association. Stroke 2003;34:1056-83.  Back to cited text no. 16
Vitale N, Renzulli A, Cerasuolo F, Caruso A, Festa M, de Luca L, et al. Prosthetic valve obstruction: Thrombolysis versus operation. Ann Thorac Surg 1994;57:365-70.  Back to cited text no. 17
Astengo D, Badano L, Bertoli D. Recombinant tissue plasminogen activator for prosthetic mitral-valve thrombosis. N Engl J Med 1995;333:259.  Back to cited text no. 18
Manteiga R, Carlos Souto J, Altès A, Mateo J, Arís A, Dominguez JM, et al. Short-course thrombolysis as the first line of therapy for cardiac valve thrombosis. J Thorac Cardiovasc Surg 1998;115:780-4.  Back to cited text no. 19
Munclinger MJ, Patel JJ, Mitha AS. Thrombolysis of thrombosed St. Jude Medical prosthetic valves: Rethrombosis – A sign of tissue ingrowth. J Thorac Cardiovasc Surg 1998;115:248-9.  Back to cited text no. 20
Renzulli A, Onorati F, De Feo M, Vitale N, Esposito S, Agozzino L, et al. Mechanical valve thrombosis: A tailored approach for a multiplex disease. J Heart Valve Dis 2004;13 Suppl 1:S37-42.  Back to cited text no. 21


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]


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