Thrombolysis of thrombosed prosthetic heart valve

77© 2016 Journal of the Practice of Cardiovascular Sciences | Published by Wolters Kluwer - Medknow
Review Article
Introduction
Prosthetic heart valve thrombosis (PHVT) is one of the
most dreaded complications of mechanical heart valves. The
incidence varies depending on the type of mechanical heart
valve and its position ranging from 0.5% to 8% per patient‑year
in the aortic and mitral position and up to 20% in the tricuspid
position. In developing countries, incidence is much higher,
even up to 10% per patient‑year.[1,2]
The incidence of PHVT is high in developing countries
and it contributes significantly to the late morbidity and
mortality after heart valve surgery. Guidelines are divided
over the best line of therapy with some (European Society
of Cardiology) recommending surgery for all, irrespective of
clinical status, while others (society of heart valve diseases)
recommend thrombolytic therapy for all patients without
contraindications. None of the guidelines have any Class I
recommendation for management of heart valve thrombosis
due to lack of randomized controlled trials (RCT). In India
and other developing countries, thrombolytic therapy is an
attractive option due to high cost and unavailability of surgery
on emergency basis in many centers. Mortality of surgery is
also considerably high varying from 5% in the New York
HeartAssociation (NYHA) Class II with up to 50% in NYHA
Class IV patients. Recent studies have shed light over various
new low‑dose, slow infusion regimens of thrombolytic agents
which are associated with equivalent efficacy as older regimens
but are safer. In this article, we review the newer regimens of
thrombolytic agents.
Risk Factors
PHVT is more common in mechanical heart valves than
bioprosthetic heart valves. It occurs more frequently in the
tricuspid than mitral position. Aortic position has a much
lesser incidence than the mitral and tricuspid valves. Bileaflet
valves have a lower incidence than the unileaflet and ball and
cage mechanical prosthesis.[3]
Suboptimal anticoagulation is
the major reason for PHVT in almost all case series. Atrial
fibrillation (AF) is a well‑recognized risk factor for PHVT.
Severe LV dysfunction is also emerging as a risk factor in
many studies.
Prosthetic Heart Valve Thrombosis: Diagnosis and Newer
Thrombolytic Regimes
Shanmugam Krishnan
Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
Prosthetic heart valve thrombosis incidence is high in developing countries and contributes to significant late mortality postvalve surgery.
Many guidelines advocate surgery as the first line therapy though thrombolysis is often used in many centers. In this article, we review
the newer regimens of fibrin‑specific thrombolytics. Newer regimens of very low‑dose, slow infusion lead to equal efficacy with lower
complication in majority of patients. Patients with the New York Heart Association (NYHA) Class I–II who have low thrombus burden
should receive thrombolysis with low‑dose slow infusion while those with high thrombus burden should be planned for surgery. Patients
presenting with NYHA Class IV should be treated with classical dose thrombolysis.
Key words: Prosthetic heart valve thrombosis, streptokinase, thrombolysis, tissue plasminogen activator
Address for correspondence: Dr. Shanmugam Krishnan,
Senior Resident, Department of Cardiology, All India Institute of
Medical Sciences, New Delhi ‑ 110 029, India.
E‑Mail: shanmugammmc@gmail.com
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DOI:
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How to cite this article: Krishnan S. Prosthetic heart valve thrombosis:
Diagnosis and newer thrombolytic regimes. J Pract Cardiovasc Sci
2016;2:7-12.
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Krishnan: Prosthetic Heart Valve Thrombosis Management
Journal of the Practice of Cardiovascular Sciences ¦ January-April 2016 ¦ Volume 2 ¦ Issue 18
Diagnosis
PHVTusually occurs in patients on suboptimal anticoagulation.
It is suspected when a patient with prosthetic heart valve
presents with dyspnea on exertion, chest pain, or embolic events.
Symptomdurationisusuallyshorterthan2 weeksinthemajority
of patients. It can present acutely as cardiogenic shock or heart
failure. On examination, one may find loss of prosthetic click,
appearance of new murmurs, or evidence of heart failure.
In high volume centers, cinefluroscopy is a quick and good
screening test as it can diagnose obstructive as well as
nonobstructive valve thrombosis in form of decreased leaflet
motion. To visualize the aortic valve in profile, left anterior
oblique view is used while mitral valve is visualized best
in right anterior oblique view. In the opposite oblique view,
base ring is positioned to yield an en face view. There is no
single technique for attaining an orientation due to surgeons’
individual variation in prosthesis orientation.
Transthoracic echocardiography
In some centers, transthoracic echocardiography (TTE) is
preferred or the only modality available for diagnosis. PHVT
may be suspected if the Doppler‑derived gradients are twice
as high as empirically found in normal prostheses. For mitral
prostheses, a mean gradient >6 mmHg and an effective
area <1.3 cm2
is suggestive of PHVT and >8 mmHg is
indicative of PHVT. For aortic prostheses, mean gradient above
30 mmHg is abnormal and indicated further investigation for
PHVT. Mean gradient >45 mmHg in absent of other causes is
considered as the criteria for PHVT.
Cine fluoroscopy (CF) and TTE are quick, effective, and
complementary diagnostic tools to diagnose PHVT in most
patients.
Once the diagnosis is strongly considered on the basis of TTE
or cinefluroscopy, transesophageal echocardiography (TEE)
helps further in confirming the diagnosis and differentiating
pannus versus thrombus. TEE also plays a role in planning
the management by calculating thrombus area and has been
incorporated in guidelines. However, TEE being an invasive
investigation, it is sometimes practically difficult to perform
in a Class IV or critically ill patient who is not on mechanical
ventilation. TTE is then useful in calculation of gradients and
response to thrombolytic therapy. In recent series, TEE was
used to assess the response to thrombolytic therapy as it can
accurately measure the thrombus area and guide in therapy.
Diagnosis is often confirmed by CF or echocardiography.
Although TTE is used for calculation of gradient and response
to thrombolytic therapy,[4]
definitive diagnosis is greatly aided
by TEE, particularly three‑dimensional echocardiography.
TEE can differentiate between pannus and thrombus unlike
CF. Calculation of thrombus area by TEE has been shown to
be predictor of embolic complications and this has now been
incorporated in guidelines.[5]
CF is an inexpensive tool available in all centers unlike TEE
and hence forms the main tool for diagnosis of PHVT in
many centers in developing countries. It may show partial or
complete restriction of leaflet movement.
Multidetector computed tomography is emerging as a
diagnostic modality with probably more precision for
differentiating between pannus and thrombus.[6,7]
Guideline recommendations
The guidelines for the management of prosthetic valve
thrombosis state [Table 1].
• TEE should be done in suspected prosthetic valve
thrombosis to assess thrombus size and valve motion
• Fibrinolytic therapy can be considered in a thrombosed
left‑sided prosthetic heart valve, which is of recent
onset (14 days) with Class I–II symptoms, and a small
thrombus (0.8 cm2
) on TEE. It is also acceptable for
right‑sided valves. For all these a period of IV, heparin is
also recommended
• Emergency surgery is recommended for a thrombosed
left‑sided prosthetic heart valve with Class III–IV
symptoms. Surgery is also recommended with a large
thrombus (0.8 cm2
).
The American College of Cardiology/American Heart
Association guidelines further state that in NYHA Class I and
II patients, it is worthwhile to switch to heparin therapy for few
days and to assess the response.[8]
Although the evidence base
is limited, it is a useful option as the risk of adverse events can
be minimized by this approach.
Clinical Trials
Trials are mostly retrospective or prospective in this population
apart from very few RCT [Tables 2 and 3]. There is also no
Table 1: Guidelines for prosthetic heart valve thrombosis
Guidelines Functional status Therapeutic strategy
ACC AHA 2014 NYHA Class III, IV
Mobile or large clot
burden (≥0.8 cm2
)
Emergency surgery
Right sided valves
NYHA Class I, II
Fibrinolytic therapy
ESC 2012[9]
Critically ill patients Emergency surgery
Severe comorbidities
or unavailability or
right‑sided valves
Nonobstructive PHVT if
complicated by embolism
or persists despite
anticoagulation
Surgery
ACCP 2012[10]
Left sided PHVT and large
thrombus area (≥0.8 cm2
)
Surgery
Left sided PHVT and
small thrombus area (0.8
cm2
)
Society for heart
valve disease
2005[11]
All patients Fibrinolytic therapy
Failed thrombolysis or
contraindications
Surgery
PHVT: Prosthetic heart valve thrombosis, NYHA: New York Heart
Association

Journal of the Practice of Cardiovascular Sciences ¦ January-April 2016 ¦ Volume 2 ¦ Issue 1 9
trial comparing different thrombolytic regimens head to head
other than a single RCT in India which compared accelerated
infusion of streptokinase (STK) with traditional dosage of
STK. Urokinase has lower success rates and hence rarely
used these days. Contrary to the traditional thinking, evidence
is emerging that most of the bleeding complications occur
early during thrombolytic infusion.[12]
Although the largest
experience is with STK, recent trials on low‑dose tissue
plasminogen activator (TPA) have shown remarkably low
incidence of embolic and hemorrhagic complications due to
slow lysis of thrombus and more fibrin selective than STK.
Case reports of successful thrombolysis with tenecteplase and
reteplase have been published.
TROIA trial was the largest cohort study of thrombolysis
for PHVT published.[13]
It was a single center study where
thrombolytic regimens were constantly reevaluated for
complications and success rates periodically. TROIA
used overall five regimens – rapid STK, slow STK, rapid
full‑dose TPA, slow half‑dose TPA, and very low‑dose slow
TPA… success of lysis was almost equal in all regimens
while complication were least in very low‑dose TPA.
It was completely TEE‑guided thrombolysis and was a
nonrandomized study and high thrombus burden cases were
likely to be sent for surgery. Repeat doses of thrombolytic were
given in event of failure or partial success. The authors found
that low‑dose TPA (25 mg over 6 h) was found to have the
lowest complication rates. Interestingly no mortality occurred
in low‑dose TPAdespite having an adequate sample size of 120
episodes. Predictors of complications by multivariate analysis
were any thrombolytic regimen other than low‑dose TPA and
a history of transient ischemic attack or stroke. Complication
rates were least in the low‑dose TPA group (10.5%) which is
much lower than the previously reported complication rates
in major cohort studies with STK. The final success rate was
comparable in all five groups – the time in which there was
good response was different – with high‑dose and classical
regimen resulted in faster opening of valve and resolution
of obstruction,… this could be crucial while thrombolysing
Table 2: Major trials with success rates and complications
Year Size Thrombolytic used Clinical
success (%)
Failure (%) Complications/
peripheral
embolism/major
hemorrhage (%)
Mortality (%) Comments
Özkan et al.[13]
1993-1997
1997-2001
16
41
STK (3 h infusion of 1.5 MU)
24 h infusion of 1.5
MU (repeat once)
68.8
85.4
37.5
24.4
12.5
2.4
Karthikeyan
et al.
2009[1]
110 STK 64.4 31/7/12 8 Only RCT
comparing
accelerated regimen
of STK
1.5 MU over 60 min or
250,000 IU over 30 min
followed by 100,000 IU/h
53.3 23/3/7 7
Sharma and
Mewada[15]
2010
48 STK (250,000 IU f/b 100,000
U/h)
81 10 6/‑/6 6
Singh et al.[16]
2010-2012
44 STK (250,000 IU f/b 100,000
U/h)
73 18 9/2.25/4.5 6.8 STK antibodies had
no effect on response
Cáceres‑Lóriga
et al.[17]
1997-2004
68 STK (250,000 IU
over 30 min f/b 100,000 IU/h
for 72 h)
85.3 8.8 22.1/7.4/2.9 5.9
Roudaut et al.[18]
1978-2001
49 STK (250000 U f/b
100,000/h)
86 11.8 25.2/15/4.7 11.8 Multiple
thrombolyitcs used
in 1/3, heparin
titration suboptimal
Initial success was
only 43% with TPA
41 UK (4500 U/kg/h for 12 h or
2000 IU/kg/h)
59
37 TPA (100 mg over 2 h)
Low‑dose (50 mg over 3 h)
68
Manteiga et al.[19]
1998
22 STK (1,500,000 IU in
90 min)
59 27 27/13.6/0 4.5 TPA used in four
patients
Gupta et al.[20]
1990-1999
110 STK (250,000 IU f/b 100,000
U/h
81.8 8.2 ‑/19.1/8.2 7.3 AF significant
predictor of
complications
Reddy et al.[21]
1990-1993
44 STK (250,000 IU f/b 100,000
U/h
88.6 11.4 16/18/6.8 4.5
Agrawal et al.[22]
1987-1997
42 STK (250,000 IU f/b 100,000
U/h
88 9.5/2.3/4.8 9.5
Silber et al.[23]
1978-1991
10 Urokinase (4000 U/kg
over 15 min f/b 4400 U/kg/h)
75 25/8.3 0 STK used in one
patient
STK: Streptokinase, AF: Atrial fibrillation, TPA: Tissue plasminogen activator, RCT: Randomized controlled trial

critically ill patient where early resolution of obstruction
could be lifesaving. In this study, the sick population was not
randomized so critical patients may have been sent for surgery
and therefore while applying the results, it is important to
remember that in a setting where thrombolysis is the primary
mode of treatment, very low slow infusion may not be prudent
for a sick high‑risk group.
Since the publication of first case report of low‑dose ultraslow
TPA,[14]
this regimen has been evaluated in a larger trial and
has shown promising results in the Ultraslow PROMETEE
trial. This trial was a prospective observational single center
study, and they analyzed 114 patients with 120 episodes of
PHVT who were thrombolysed with low‑dose TPA 25 mg
which was given over 25 h. Eight sessions were given in case
of failure after session with heparin overlap for 6 h between
consecutive sessions. Results were notable with remarkable
success rates of 90% (85–95%). Mean dose of TPA required
was 64 ± 48 mg. Recurrence occurred in six patients (6.3%).
Significant predictors of thrombolytic failure were higher
NYHA class at presentation, AF, and duration of suboptimal
anticoagulation, valve area, and thrombus area. On multivariate
analysis, only higher NYHAclass was the significant predictor.
Complications occurred mainly during the initial sessions
and there were four nonfatal major complications. Only
one patient died due to refractory heart failure. Predictors
of complications were higher NYHA class, AF, duration of
suboptimal anticoagulation, and higher thrombus area. Major
limitation of the study was that NYHA Class IV patients
were underrepresented and these patients did not have a good
outcome.
All recent trials of newer fibrin‑specific thrombolytics have
shown encouraging results in success rates and fewer embolic
events, major hemorrhages, and thus mortality.
Success rates vary widely between 60% and 90%. Success
rates defined in earlier studies did include patients with
complications also unlike in recent studies. It is clear from
studies that low‑dose TPA and ultraslow low‑dose TPA have
minor embolic complications due to slow lysis and lower
bleeding complications than STK infusion. However, for
NYHA IV patients, immediate surgery or thrombolysis is
needed, hence accelerated regimens would be the better choice
though low‑dose TPA has been successful in TROIA trial.
Thrombolysis Versus Surgery
There is no RCT comparing thrombolysis to surgery in
PHVT. Most of the data are obtained from observational
studies. A meta‑analysis conducted by Karthikeyan et al.
which compared studies comparing surgery to thrombolysis
found that surgery resulted in complete success more than
thrombolysis though the difference was not statistically
significant.[29]
Mortality was not significantly different between
the two groups though numerically it was more in the surgery
group. Complications such as systemic embolism, major
bleeding, and rethrombosis all occurred significantly less in
the surgery arm. Thus, they concluded that surgery is better
than thrombolysis.
Castilho et al. conducted a meta‑analysis which included
all studies comparing thrombolysis and surgery found
that mortality was significantly lower in thrombolysis arm
Table 3: Major trials with fibrin specific agents
Year Size Thrombolytic used Clinical
success (%)
Failure (%) Complications/
peripheral
embolism/major
hemorrhage (%)
Mortality (%) Comments
Sharma et al.[24]
2012
10 Tenecteplase (1 mg/kg) 90 0 0 0 Partial success
achieved in all patients
Özkan
et al.[25]
2009-2013
120 Ultraslow low‑dose TPA
(25 mg over 25 h)
90 (85-95) 10 6.9/1.7/2.5 0.1 Lowest incidence of
complications
Özkan et al.[13]
2001-2002 12 TPA (10 mg bolus 90 mg
over 5 h)
75 33.3 16.7
2002-2005 27 TPA (6 h infusion of 50 mg) 81.5 29.6 3.7
2005-2009 124 TPA (25 mg without a
bolus, repeat six times)
85.5 10.5 0
Renzulli et al.[26]
1991-1994
20 TPA 70 30/30/0 0 All patients had
successful valve
opening
Teshima et al.[27]
1998-2001
27 TPA 55.6 22.2 3.7/3.7/0 0 Urokinase used
in 22 patients as
additional therapy
Ari et al.[28]
2015
8 TPA (25 mg over 6 h) 100 ‑ ‑ ‑
TPA: Tissue plasminogen activator

Journal of the Practice of Cardiovascular Sciences ¦ January-April 2016 ¦ Volume 2 ¦ Issue 1 11
than surgery arm (6.6% vs. 18.1%).[30]
They also showed
that surgical mortality was lower in the two‑arm studies in
centers where both procedures are done at the discretion of
the physician unlike in the one arm centers where surgery
is the preferred treatment modality (12.6% vs. 20.6%).
Similarly, thrombolysis mortality was significantly lower
in the single‑arm group where thrombolysis is the preferred
treatment modality for all patients (6.1% vs. 10.8%). The rate
of embolic events was higher in the thrombolysis arm though
the rates of stroke were similar in both the arms. Intracranial
hemorrhage occurred only in the thrombolytic arm.
Thus, a RCT only will provide the definite answer to whether
thrombolysis or surgery is better. Two such RCTs are already
ongoing.
Conclusion
Approach could be to individualize the treatment depending
on NYHAclass, thrombus burden, and availability of surgery.
Newer regimen of very low‑dose, slow infusion leads to equal
efficacy with lower complication in majority of patients.
However, the response time is longer and TEE guidance is
mandatory during the treatment.
NYHA Class I‑II who have low thrombus burden should
receive thrombolysis with low‑dose, slow infusion while those
with high thrombus burden should be planned for surgery as
risk of surgery is likely to be lower (5–10%) versus risk of
complication of thrombolysis (15–20%). In patients presenting
with NYHAClass III, decision is to be individualized based on
thrombus burden. Patients presenting with NYHAClass IVand
cardiogenic shock/heart failure to be treated with classical dose
thrombolysis as time is of essence here and surgical mortality
is very high (50%).
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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