1. Left sided prosthetic thrombosis

2. Epidemiology Obstruction of prosthetic heart valves may be caused by thrombus formation, pannus ingrowth, or a combination of both. Mechanical prosthetic heart valve thrombosis has a prevalence of only 0.3% to 1.3% per patient-year in developed countries but is as high as 6.1% per patient-year in developing countries.

3. Epidemiology Thromboembolic complications, including systemic emboli, are more frequent and occur at a rate of 0.7–6% patient years. Non-obstructive PVT is a relatively frequent finding in the postoperative period, with a reported incidence as high as 10% in recent transoesophageal echocardiography (TOE) Studies.

4. Epidemiology Obstruction of a tricuspid mechanical prosthesis is 20 times more frequent than left- sided PVT. Similarly for haemodynamic reasons, mitral PVT is 2–3 times more frequent than thrombosis of an aortic prosthesis.

5. Risk factors 1- Atrial fibrillation. 2- Previous thromboembolism. 3- Left ventricular dysfunction (LVEF < 30%). 4- Mechanical mitral or tricuspid prosthesis. 5- Older-generation thrombogenic valves (e.g. Starr-Edwards, and mechanical disc valves). 6-Those with demonstrated thrombotic problems when previously off Warfarin therapy. 7- More than one mechanical valves. 8- Hypercoagulable state.

6. Diagnosis The clinical presentation of PVT is highly variable, often depending on the presence or absence of obstruction. Severe obstructive PVT is typically associated with overt heart failure, whereas non-obstructive PVT is often an incidental finding or can present as an embolic episode. Partial obstruction (for example, obstruction of one leaflet) can manifest itself with abnormal dyspnoea, or systemic embolism.

7. muffling or disappearance of prosthetic sounds. appearance of a new regurgitant or obstructive murmur.

8. Diagnosis The initial diagnostic work-up includes a transthoracic echocardiogram (TTE) and cinefluoroscopy of mechanical valves. TOE will often be performed to complete the investigation.

9. Echocardiography Abnormal transprosthetic flow (aliasing or central regurgitation flow). Transprosthetic gradients and effective orifice area are determined using continuous Doppler. Pulmonary artery pressures should also be measured. Abnormal movement of the prosthesis (immobile hemi-disc, incomplete or delayed opening) visualisation of a paraprosthetic thrombus.

11. Echocardiography For mitral prostheses: Mean gradient 8 mm Hg Effective area less than 1.3 cm2 Peak E velocity >1.9 m/s, VTImitral/VTIaortic >2.2, Pressure half-time >130 ms

12. Echocardiography For aortic prostheses Mean gradient >45 mm Hg Obstructive index <0.25

13. PPM or malfunction In the case of small size aortic prostheses (for example, mechanical valve sizes 19 or 21), Against a diagnosis of PVT: An already elevated gradient on previous echocardiographic examinations, Obstructive index >0.25, Effective orifice area >0.7 cm2, Valvular resistance,280 dynes.s.cm25, Normal leaflet mobility on cinefluoroscopy

14. Thrombus or pannus Pannus: Usually annular in location. More frequent on aortic than on mitral prostheses. Typically presenting as a very dense immobile echo, Typically encountered in patients with a normal anticoagulation profile and with subacute or chronic symptoms.

15. Thrombus or pannus PVT: Immobility or reduced leaflet mobility, Presence of thrombus on either side of the prosthesis, with or without obstruction Disappearance of the normal physiological prosthesis regurgitant flow Presence of central prosthesis regurgitation Pronounced spontaneous echo contrasts in the left atrium

19. Management of left sided prosthetic thrombosis

20. Optimal treatment of left-sided PVT is unclear - Anticoagulation -Fibrinolysis -Surgery

21. Absence of randomized controlled trials Guidelines differ in their recommendations regarding the choice of treatment for PVT

25. Surgery Urgent or emergency valve replacement is recommended for obstructive thrombosis in critically ill patients without serious comorbidity. (recommendation class I, level of evidence C)

26. Fibrinolysis Critically ill patients unlikely to survive surgery because of comorbidities or severely impaired cardiac function before developing valve thrombosis. Situations in which surgery is not immediately available and the patient cannot be transferred. Thrombosis of tricuspid or pulmonary valve replacements, because of the higher success rate and low risk of systemic embolism.

27. Thrombolysis protocole Short protocol : Intravenous recombinant tissue plasminogen activator 10 mg bolus + 90 mg in 90 minutes with UFH, or Streptokinase 1 500 000 U in 60 minutes without UFH.

29. Surgery should be considered for large (≥10 mm) non-obstructive prosthetic thrombus complicated by embolism (recommendation class IIa, level of evidence C) or which persists despite optimal anticoagulation. Fibrinolysis may be considered if surgery is at high risk.

32. Although fibrinolytic therapy of a left-sided obstructed prosthetic heart valve is associated with an overall rate of thromboembolism and bleeding of 17.8%, the degree of risk is directly related to thrombus size.

33. Patients with a small thrombus ( 1.0 cm diameter or 0.8 cm2 in area) have a 2.4–fold higher rate of complications per 1.0 cm2 increase in size.

34. Risk factor for fibrinolytic therapy Active internal bleeding, History of hemorrhagic stroke, Recent cranial trauma or neoplasm Diabetic hemorrhagic retinopathy, Large thrombi, mobile thrombi, systemic hypertension(>200 mm Hg/120 mm Hg), Hypotension or shock, NYHA class III to IV symptoms

35. Fibrinolysis With mild symptoms due to aortic or mitral valve thrombosis with a small thrombus burden, it is prudent to reassess after several days of intravenous UFH. If valve thrombosis persists, fibrinolysis with a recombinant tissue plasminogen activator dose of a 10 mg IV bolus followed by 90 mg infused IV over 2 hours is reasonable.

36. Fibrinolysis Heparin and glycoprotein IIb/IIIa inhibitors are held, but aspirin can be continued. A lower tissue plasminogen activator dose of a 20 mg IV bolus followed by 10 mg per hour for 3 hours may be appropriate in some situations. Alternatively, streptokinase may be used with a loading dose of 500,000 IU in 20 minutes followed by 1,500,000 IU over 10 hours.

37. If fibrinolytic therapy is successful, it is followed by intravenous UFH until VKA achieves an INR of 3.0 to 4.0 for aortic prosthetic valves and 3.5 to 4.5 for mitral prosthetic valves.

38. Surgery vs fibrinolysis Surgical treatment of a thrombosed prosthetic Heart : success rate close to 90% Fibrinolytic therapy: 70% success rate

39. Surgery vs fibrinolysis There was no difference in mortality between surgical and fibrinolytic therapy for left-sided prosthetic valve thrombosis, Surgery was associated with lower rates of thromboembolism (1.6% versus 16%), major bleeding (1.4% versus 5%), and recurrent prosthetic valve thrombosis (7.1% versus 25.4%)

40. systematic review and meta-analysis of the available literature comparing emergency surgery with FT for left-sided PVT

44. Characteristics of recently published Review and Metaanalyses 1: Bonou et al, EHJ Acute cardiovascular Care,2012, 3: Huang et al, JACC,2013 2: Karthikeyan et al, EHJ,2013 4: Castilho et al, J Thromb. Haemost. 2014

45. - Systematic review (2013) -Forty-eight studies were included (2302 patients).-No randomized studies was identified, and all were observational in design

46. mortalityEmbolic event StrokeSuccessbleedingDeath or stroke surgery18.1%4.6%4.3%81.9%4.6%19% FT6.6%12.8%5.6%80.7%6.8%11.4%

47. Conclusion - Mortality in patients treated by thrombolytic therapy for valve prosthesis thrombosis is significantly lower than in patients treated surgically. -In addition, in our meta-regression, NYHA class IV was associated with mortality in the surgical group, but not in the thrombolytic group -As we cannot yet ascertain whether this difference is due to the treatment alone, more studies are now necessary to further clarify these findings

48. Metaanalytic reviews dictate to establish a new treatment strategies

50. Surgery has been the traditional management of PVT, but thrombolysis has been proposed as first line of therapy Thrombolytic therapy in recent years apears to have high success rate with relatively with low complication and mortality

51. New thrombolytic therapy protocols? (Why low-dose, slow infusion of tPA?)

53. Comparison of different TRansesophageal echOcardiographic guided thrombolytIc regimens for prosthetic vAlve thrombosis: (The TROIA Trial) A 16-year study in a single center, prospective 220 episodes, 5 different thrombolytic regimens, Group 1- Rapid SKZ (1.5 mU,3 hours): 1993-1997 Group 2- Slow SKZ (1.5 mU, 24 hours):1997-2001 Group 3- 100 mg tPA ( 5 hours):2001-2002 Group 4- 50 mg tPA ( 6 hours ):2002-2005 Group 5- 25 mg tPA ( 6 hours, without bolus, without concomitant UFH, repetitive up to 150 mg ):2005-2009 Overall success rate % 82, (for Group 5: 85%) Özkan et al, J Am Coll Cardiol CV imaging, 2013

54. The overall success did not differ significantly among Groups I through V. Although the overall complication rate was similar among Groups I through IV, it was significantly lower in Group V. The combined rates of mortality and nonfatal major complications were also lower in Group V than in the other groups. There was no mortality in Group V

55. CONCLUSIONS Low-dose slow infusion of t-PA repeated as needed without a bolus provides effective and safe thrombolysis in patients with prosthetic valve thrombosis.

57. Ultra-slow thrombolytic therapy: A novel strategy in the management of PROsthetic MEchanical valve Thrombosis and the prEdictors of outcomE: The ultra-slow PROMETEE trial Mehmet Özkan, Sabahattin Gündüz, Ozan Mustafa Gürsoy, Süleyman Karakoyun, Mehmet Ali Astarcıoğlu, Macit Kalçık, Ahmet Çağrı Aykan, Beytullah Çakal, Zübeyde Bayram, Ali Emrah Oğuz Emre Ertürk, Mahmut Yesin, Tayyar Gökdeniz, Nilüfer Ekşi Duran, Mustafa Yıldız, Ali Metin Esen European Heart Journal (under review)

58. The ultra-slow PROMETEE trial The safety and efficacy of 25 mg tPA/6 hours infusion has been established in TROIA trial. Further prolongation of the TT regimen may be associated with lower complication rates without compromising efficacy Between 2009-2013, 114 patients, 120 episodes 25 mg tPA/ 25 h infusion (without bolus, without concominant UFH) 6 h of UFH infusions between tPA sessions Maximum 8 episodes (200 mg) Ozkan et al, European Heart Journal (under review)

59. The ultra-slow PROMETEE trial Total success : 90 % Total complications: 6,7 % (in the TROIA Trial : 10.5%) (Non-fatal major complications: 3,3 %) - Cerebral embolism (n:1, 0,8 %) -İntraabdominal bleeding (n:1, 0,8 %) -GIS bleeding (n:1, 0,8 %) -Periferal embolism (n:1, 0,8 %) - No intracranial bleeding (Minor complications: 2,5 %) - Intraabdominal bleeding without need for Tx (n:2, 1,6 %) - Vaginal bleeding (n:1, 0,8 %) Mortality : %0,8 Ozkan et al, European Heart Journal (under review)

60. Univariate predictors of thrombolytic failure (for the ultra-slow PROMETEE Trial) YESNO Atrial fibrillation Pregnancy NYHA class IV status * Stroke or transient ischemic attack Higher baseline thrombus area Nonobstructive/obstructive thrombus Smaller valve area Age (years) Greater duration of suboptimal INR Elapsed time since valve surgery (months) Gender Hypertension Diabetes mellitus Aspirin use Thrombus site Clinical presentation Make of valve * :independent predictor Ozkan et al, European Heart Journal (under review)

61. ‘‘Thrombolytic therapy with low-dose (25 mg) and slow infusion (6 to 25 hours) of tPA is a miracle’’

63. CASE : OBSTRUCTIVE THROMBOSIS 29 year-old, 30 weeks of pregnancy Mechanical MVR 11 year ago Dyspnea (NYHA Class IV) No sound of closing of mechanical valve INR: 1.2 on admission, MVA: 0.6 cm2 ; Grad: 29mmHg(mean)

66. Low dose slow tPA infusion (75mg)

69. NON-OBSTRUCTIVE THROMBUS 41 year-old, female 2006- MVR Presentation: TIA Admission INR: 1,2 Cranial CT: Normal MVA:2,9 cm 2,Mean Grad:7mmHg

72. After 25 mg tPA infusion for 25 hours