Discussion
The lower velocity of flow in the right heart and the commonly larger
size of TV prosthesis, makes thrombus formation easier. Moreover, RV
dysfunction, atrial fibrillation, right atrial enlargement, pulmonary
arterial hypertension, hypercoagulable state, and multiple prostheses
are other common predisposing factors; therefore, biological valves were
assumed as the gold standard and mechanical valves as the challenging
device in TV position [8,10-12]. However, mechanical valve has been
used more frequently due to its presumed longer durability in the case
of adequate anticoagulation maintenance, and higher risk for redo
surgery in these patients, as they usually have a history of multiple
sternotomies owing to previous TV repair, frequent other valve
replacements, or congenital heart surgeries [13,14]. The present
report is the largest and the most comprehensive single-center study
evaluating the isolated mechanical TV thrombosis with respect to
treatment modalities and response to therapies during follow up period.
Our patients have encountered this serious and morbid condition after an
average elapsed time from surgery of 49.9 (range 0.4-276) months, while
29.8% of episodes occurred in ≤12 and 46.2% in ≤24 months following
surgical TV replacement. This is almost in agreement with previous
studies evaluating the rate and prognosis of TV thrombosis. Roudaut et
al. [11] described a median time from valve replacement to
thrombosis of 4.3 years (14 days to 18 years) and an incidence rate of
thrombosis in 24% of patients in the first postoperative year. In a
meta-analysis by Liu et al. [10] valve thrombosis occurred at a mean
follow-up of five to seven years and structural bioprosthetic
degeneration occurred at an average of seven to nine years after TV
replacement. These findings emphasize the importance of adequate
anticoagulant treatment with a special consideration of postoperative
period as well as during follow-up period.
The sub-therapeutic INR values less than 3 and 3.5 was seen in 70% and
82% of episodes at the time of admission, respectively. As it could not
be the only clue to anticoagulation status, due to a probable more
chronic process of a usually multilayered clot, we also assessed the
average amount of previous 3-6 months. Contrary to left-sided valves,
guidelines do not specify recommended levels of INR for mechanical
prosthesis in TV position. It is advocated that target INR should be
adjusted to patient risk factors and the thrombogenicity of the
prosthesis (i.e., mitral or tricuspid position, atrial fibrillation, and
a history of previous thromboembolism). In addition, a single INR target
is mandatory for efficient antithrombotic therapy to identify that the
acceptable range is 0.5 units of INR levels on each side, avoiding the
upper or lower edge of the range values. We could not determine such a
target due to our study type, but according to guidelines implications
and considering the valve type in our study, we recommend the INR target
of at least 3 for lower risk patients and 4 for higher risk ones with a
history of previous thrombosis [3,4] Shapira et al. [15]
recommended the target level of INR as 3.5-4 for patients with TV
prostheses, and Zhang et al. [16]
considered the target INR levels of 3-3.5. On the other hand, we should
also take into account that patients may have lesser compliance with
higher INR goals [17]. In addition, Aspirin 75 to 100 mg daily in
combination with vitamin K antagonist anticoagulation in all patients,
and the continuation of warfarin with a therapeutic INR levels in
patients undergoing minor procedures is recommended to prevent the rapid
decrease in the INR and the risk of thromboembolism [3,4].
Complete hemodynamic and clinical success rate of 68.2% following
thrombolytic therapy was observed in this study. It is fairly within the
ranges of previous similar studies [7,9,14,18,19]. It should be
considered that different success rates may be possibly caused by
different patient selection, diagnostic modalities, fibrinolytic
regimens [20], and the definition of outcomes. Additionally, most of
our cases (97%) were diagnosed as obstructive TV thrombosis, and we
evaluated successful response in absence of important complications
(such as retroperitoneal hematoma and stroke). There was no
statistically significant difference regarding the success rate among
thrombolytic treatment subgroups. This might be due to insufficient
number of cases in certain subcategories [20].
Our study highlighted that thrombolytic response depends on the
chronicity of thrombosis and the presence of pannus formation. We should
bear in mind that valve thrombosis could be an acute, subacute or
chronic event and thrombi are typically formed of different clot layers,
with variable degrees of organization. This indicates that trying
thrombolytic therapy as the first step treatment is sensible in most
patients, even though probably with an incomplete resolution of clot
[11,12]. In addition, regarding the treatment strategy in recurrent
cases, it seems that the prior management of patients had a substantial
impact on treatment choice by physicians. In those with a history of
prior thrombolysis and anticoagulant intensification there were more
trends towards surgery, while in patients with previous TV surgery, more
patients were treated with fibrinolytic. In a former study in cases
received fibrinolytic, it was revealed that the level of anti-tissue
plasminogen activator antibodies (ATA) may increase during thrombolysis
with rt-PA infusion and may interfere with the success rate,
necessitating a higher dose for complete success and play a role in
resistance to fibrinolysis [21].
Retroperitoneal hematoma may happen unexpectedly in patients under
anticoagulant treatment. It may be life-threatening and leads to
abdominal compartment syndrome, requiring prompt surgical approach
[22]. The lowest non-cerebral major bleeding was reported to be
1.7% by Ozkan et al. [23] with ultraslow thrombolytic therapy.
Moreover, we found an embolic cerebrovascular event during thrombolytic
therapy, in spite of being primarily unpredictable in right sided PVT
fibrinolysis. Cerebral embolism following thrombolytic treatment have
been reported to have an incidence of 3-10% and is even more frequent
in the presence of atrial fibrillation [20]. This heighten the role
of TEE in risk stratifying of patients for thrombolysis. Given the high
rate of left-sided valve replacements, congenital heart disease and AF
rhythm among TVR patients, they should be evaluated for the presence of
thrombus formation on left-sided prosthetic valves, left atrium or its
appendage, and probable PFO as the source of emboli, as well.
Moreover, despite the low rate of mortality and major non-fatal
complications in the course of in-hospital management, there were
considerable recurrent episodes throughout the entire follow-up period.
Thirty-eight percent of our patients experienced at least one episode of
recurrent TV thrombosis. Recurrence rates after thrombolytic therapy
were reported from 11% to 32% in similar studies [18,21,24] and
fibrinolysis was associated with a significantly higher rate of
recurrence, though none of previous reports has described in isolated
mechanical TV thrombosis [18] According to our findings, it seems
that incomplete resolution of thrombosis and the presence of pannus are
remarkable triggers for re-thrombosis. We should mention the “Doppler
silent” phenomenon, which implies that complete or acceptable
normalization of valve occluder movement on fluoroscopy and valve
gradients on echocardiography may not be merely the conclusive signs of
complete thrombus resolution, and further visualization by TEE seems to
be essential [25] So, a considerable number of our patients might
have needed the continuation of thrombolysis as TEE was not performed in
a significant number of patients.
Finally, novel diagnostic and therapeutic approaches are still evolving.
Sixty-four-slice multi-detector computed tomography proved to be helpful
in identifying masses amenable to thrombolysis in patients with
prosthetic valve dysfunction. A high attenuation suggests pannus
overgrowth and is associated with reduced response to fibrinolysis,
whereas a lower value is associated with thrombus formation [26].
With regard to treatment, catheter‐directed thrombolysis in selected
patients may render the potential advantage of local thrombolysis with a
much lower dose than systemic therapy, possibly providing better
efficacy while reducing the risk of bleeding complications
[8,16,27]. The selection of type of prosthetic valve is another
important issue, so that the availability of transcatheter
valve-in-valve replacement can change the trade-offs between mechanical
and bioprosthetic valves [3]. Tricuspid valve-in-valve procedure was
shown to be technically feasible in a number of studies in patients with
a wide range of valve size [13,28]. This will be more interesting
when we consider the relatively short average time to thrombosis and a
high recurrence rate in our study together with the data derived from
former studies indicating mean reoperation time of 44.2 months for
mechanical prosthesis [29].