Key words
post-thrombotic syndrome - deep vein thrombosis - predictive factors - anticoagulation
- compression - thrombolysis
Schlüsselwörter
Post-thrombotisches Syndrom - tiefe Beinvenenthrombose - prädiktive Faktoren - Antikoagulation
- medizinische Kompression - Thrombolyse
Post-thrombotic syndrome prevalence and assessment
Post-thrombotic syndrome prevalence and assessment
Post-thrombotic syndrome (PTS), being the late sequalae of the deep vein thrombosis
(DVT) concerns from 10 to 70 % of lower leg DVT patients [1], [2], [3]. Among the factors influencing the reported PTS prevalence, both, the
potentially predictive factors as well as the way of PTS evaluation and assessment
should be mentioned [1], [2], [4]. Among the
methods used to diagnose PTS as well as to assess the PTS severity, various tools
and criteria were used [4].
In the recent years, the majority of the performed studies used the Villalta score
based on the venous disease symptom and signs assessment for PTS presence and
severity evaluation [4], [5]. An implementation of this score for PTS
assessment has been recommended by the International Society on Thrombosis and
Hemostasis, however, its weakness as well as unspecificity as an objective tool for
diagnosing and PTS scoring is recently discussed and criticized [6]. In term of the proper planning of further
research, current PTS diagnostic criteria should be probably revised. There are
other scores, like Ginsberg criteria or Brandjes score, as well as the scores
commonly implemented in the chronic venous disease evaluation (such as CEAP, rVCSS),
but they neither seem to be sufficient.
Post-thrombotic syndrome predictive factors
Post-thrombotic syndrome predictive factors
Looking for the PTS predictive model, various groups of the factors should be
evaluated, including the factors related to the patient initial status
(characteristics of the patient), the factors related to the initial DVT episode,
as
well as the factors related to the way of the treatment [1], [2], [4].
DVT recurrence: One of the major factors influencing on the PTS occurrence is
the ipsilateral thrombosis recurrence leading to the 2–10 times higher risk of PTS
[2], [3],
[4], [7].
Knowing this, the proper anticoagulant treatment oriented to reduce the recurrence
risk, always considering the risk/benefits ratio of the anticoagulant treatment is
crucial [8].
Anticoagulation: It is important to respect the minimal duration, at least
3 months’ anticoagulation in the patients with temporary risk factor and longer or
life-long therapy in unprovoked DVT cases [2],
[3], [4] and
the sufficient dose, specially in the first 3 months. Duration of the
anticoagulation treatment longer than standard by itself seems not to influence the
risk of PTS occurrence, provided the proper duration of the anticoagulation is
respected. The value of insufficient intensity of anticoagulation in patients on
vitamin K antagonists (subtherapeutic INR values) is emphasized, especially during
the first 3 months of the therapy [4], [9], [10], [11], [12], [13]. On the other hand, there is no clinical
confirmation that a high intensity of anticoagulation over the therapeutic value
results in a lower PTS rate [12], [13]
Patient: Among the risk factors related to the patient initial status, the
most important are the age of the patient by the time of the thrombosis, obesity as
well as previous chronic venous disease presence. The older age of the DVT patient
is related to an increased PTS risk (with 30 % to the 3-fold higher PTS rate) [2], [3], [4]. The relationship between obesity and chronic
venous disease (CVD) symptoms as well as disease progression is well known from
studies concerning the primary venous disease. In DVT patients, the presence of
obesity leads to the more than 2-fold increase in PTS rate [2], [3], [4]. Another important factor related to higher PTS
occurrence is the presence of varicose veins already before the DVT onset [3], [4].
Preexisting varicose veins in DVT patients resulted in at least 2-fold increase of
PTS rate [4]. On the other hand, according to
several studies up to 40 % of all diagnosed PTS might be related at least in part
to
a preexisting chronic venous disease [14].
Thrombophilia [3], [4], [15] or gender [2], [3], [4] was not related to higher PTS rate.
Causes and clinical manifestation of DVT: PTS can be found in both,
symptomatic and asymptomatic DVT courses [1], [3], [4]. There is
also no significance difference in the PTS prevalence between a provoked and
unprovoked DVT etiology [1], [3], [4]. In term of
the DVT location, the higher prevalence of the PTS is reported in patients with a
proximal lower leg DVT. However, the risk of the PTS occurrence is also present in
distal, calf vein, DVT cases [1], [3], [4].
Residual Thrombus: The presence of the residual DVT symptoms during the
treatment course as well as the presence of the residual thrombotic changes in the
vein in duplex investigation during the follow up period, seem to be the important
factors influencing on the final treatment outcome [1], [3]. Residual thrombosis presence
after DVT treatment increase the risk of PTS occurrence at least 1.6 times in the
patients treated conservatively [1]. A recent study
by Comerota et al. documented the statistically significant correlation between
residual thrombosis after catheter directed thrombolysis treatment and PTS
occurrence in the ilio-femoral DVT [16].
Despite the performed research, in the available literature, many questions regarding
the PTS predictive factors remain still unanswered. Further research dedicated to
the validated PTS predictive model creation should be based on objective PTS
criteria and assessment methods.
Post-thrombotic syndrome predictive models
Post-thrombotic syndrome predictive models
An increasing knowledge and research dedicated to the potential PTS predictive
factors resulted in the PTS predictive model construction. The main goal of this
models is the possibility to select the patients at highest risk of PTS occurrence.
Their clinical efficacy needs to be proven in further research on larger groups of
patients.
In the Canadian VETO study (Venous Thrombosis Outcomes) 359 DVT patients were
evaluated [17]. Clinical assessment was performed
at baseline, and at 1, 4, 8, 12 and 24 months. PTS positive predictive factors were:
age, previous DVT episode, atherosclerosis risk factor presence [hypertension, high
cholesterol, higher BMI], longer duration of symptoms before DVT diagnosis and work
in a job with high physical demands. Among the factors not influencing the PTS
occurrence the following were identified: sex, location of DVT (proximal vs.
distal), side of DVT (left vs. right), type of DVT (cancer-related, temporary risk
factors [e. g. surgery, trauma] or idiopathic), initial anticoagulation with LMWH
or
UFH, or duration of warfarin therapy.
Van Rij et al prospectively analyzed the clinical outcome of 114 acute DVT patients
[18]. Within 7 –10 days after DVT diagnosis all
the patients underwent a further review with clinical examination, ultrasound and
air plethysmography with subsequent follow up examinations up to 5 years. The
following factors were identified as the best predictors for PTS occurrence:
extensive clot load on presentation; < 50 % clot regression at 6 months; venous
filling index > 2,5 mL/sec and abnormal outflow rate (< 0.6). Patient with
three or more of this factors had a significant risk of developing PTS with
sensitivity of 100 % and specificity 83 %.
In the post hoc analysis of the SOX trial cohort, the SOX – PTS index was calculated
and proposed [19]. The high predictors of the PTS
occurrence were the following factors from the baseline assessment: iliac vein DVT
(1 point), BMI > 35 [2], Villalta score 9–14 at
baseline [1], Villalta score > `14 at baseline
[1]. According to this model, the score ≥ 4 is
related to almost 6 fold increase of the PTS risk [OR 5.9 (95 % CI 2.1–16.6)].
In the model published in 2018 by Amin et al. not only the baseline risk assessment
but also the risk assessment in the subacute phase was proposed (6 months after DVT
diagnosis) [20]. Concerning the baseline
assessment, the age > 56 years (2 points), BMI > 30 [2], varicose veins [4], smoking [1], female sex [1], provoked DVT [1], ilio-femoral DVT [1], positive DVT
history were selected as the clinically important. The score 3–4 from the baseline
assessment reflected 30 % risk of PTS occurrence; in the patents with 5 point score
the clinical probability was at the level of 40 %. In the secondary model (secondary
evaluation performed 6 months after DVT onset) among the factors of the greatest
importance for PTS occurrence the following were found: age > 56 years [1], BMI > 30 [1], varicose veins presence [3], smoking
[1], residual vein obstruction [1]. In patients with a secondary assessment score of
3–4 points the PTS risk was 45 % and for the score of 5 points it was 60 %. For now,
the models proposed and described above allow to predict the clinical PTS
probability only. According to the current research, we are probably still not able
to predict (on the individual basis) which of the patient will and which will not
develop PTS after a DVT episode. Further research is also needed in this area,
especially the research based on the proper objective methodological criteria
regarding PTS diagnosis and severity assessment which are still lacking and have to
be developed.
Post-thrombotic syndrome prevention methods
Post-thrombotic syndrome prevention methods
An avoidance of DVT occurrence remains the best way of the PTS occurrence prevention
[1]. Unfortunately, despite the number of
guideline documents dedicated to the various patient populations we still do not
know measures which allow to avoid all DVT cases (even, if with the properly
implemented antithrombotic prophylaxis protocols, the DVT risk only significantly
decreases) [21], [22], [23], [24]. Among the other important factors related to the still high DVT
prevalence are: the growing age of the population, the lack of the proper VTE
awareness among the medical staff as well as in the patient populations and also the
gap between the guideline recommendation and “real world” clinical practice.
As previously mentioned, in the patients with already present DVT, some PTS
predictive factors can be identified, but the final DVT episode outcome remains
difficult to predict in term of the PTS occurrence in the single particular patient
case. According to the performed research, to lower the risk of PTS occurrence in
the post-DVT patients, some clinical attempts have been proposed including
compression use, anticoagulation treatment modification or an invasive early vein
lumen reopening. On the other hand, we do not know if the modification of the other
PTS risk factors (such as obesity or previous chronic venous disease) in the disease
course can result in the PTS rate reduction.
Compression stocking in PTS prevention
Compression stocking is one of the important compounds of the DVT patient
treatment algorithm, facilitating the patient mobilization as well as lowering
the severity of the local complains (including DVT related pain and leg
swelling). In the current literature at least six RCTs reported benefits of
compression in reducing incidence of PTS [25],
[26], [27], [28], [29], [30]. As found out in the
randomized controlled study performed by Prandoni and coworkers, the use of the
below knee class II compression stocking in DVT patients within a 2 years period
after the DVT episode, reduced the PTS prevalence in the late follow up phase
from 49 % in the control to 26 % in the compression group (mean follow up
duration 49 months [26].
Brandjes et al randomized 194 patients with proximal symptomatic DVT into two
groups: one wearing 30–40 mm Hg knee length compression stockings or to the
control group, without stockings. In the follow up period (mean 76 months) 50 %
reduction in the PTS occurrence in the stocking group was noticed [25]. In the study of Blättler and Partsch the
early mobilization of the DVT patients wearing compression stockings resulted in
significant reduction of local complains as well as lower postthrombotic
syndrome rate in the late follow up phase [31].
Despite the data from several previously published RCTs, after the SOX trial
result publication (comparison of the efficacy of the class II below the knee
compression stocking with placebo stocking), the role of the compression in the
PTS prevention started to be questioned [32].
According to the SOX trial results, the comparison of both groups did not result
in the statistically significance difference in the PTS rate (assessed by
Ginsberg criteria) between the groups (cumulative PTS rate 14.2 %/active ECS/vs.
12.7 %/placebo ECS/(HR 1. 13; 95 % CI 0.73–1.76; p = 0.58). Several
methodological problems related to the SOX trial were discussed after the study
result publication, specially the fact that the start of the use of compression
was relatively late in both groups and that the compression stockings were send
by post and nobody introduced the patient to the skills of putting them on the
leg. Compliance, as one could expect in consequence, was very low in both
groups. On the other hand, on the base of these results in many (after SOX trial
era) guideline documents, the use of the compression in PTS prevention was not
recommended (ACCP 2016) [1], [8].
The Cochrane analysis published in 2017 on the base of 10 RCT analysis suggests
(with a low level of evidence) that the patients with DVT who wear elastic
compression stockings are less likely to develop PTS RR 0.62 (95 % CI
0.38–1.01), although no significant differences concerning severe PTS occurrence
were observed (RR 0.76 (95 % CI 0.53–15) [33].
The authors of the most recent (2017) guidelines concerning the use of medical
compression stocking (MCS) in venous and lymphatic disease downgraded the
recommendation for the PTS prevention by MCS in acute DVT. Compression is
recommended not only to decrease pain and swelling in DVT, as well as to
mobilize the patient, but also to prevent post-thrombotic syndrome occurrence
(this last indication recommendation grading was changed from 1 A in the
previous guidelines to 1B in the current document) [34].
Concerning the use of the compression in DVT patients, both, the compression
class as well as duration of the compression use are also still not precisely
defined. In the IDEAL DVT Study (based on the group of 865 patients with DVT),
the individualization of the compression treatment duration was proposed. The
shortening of the compression use to 6 month therapy in some of the investigated
patients (based on the Villalta score assessment) resulted in the same clinical
outcome as the continuous 2 year therapy [35].
As a consequence of the data analysis further studies on the compression in PTS
prevention are needed with the proper way of PTS assessment. In daily practice,
in most of the currently treated DVT patients, the compression is used at least
in the acute DVT phase to reduce the swelling and local complains. The role of
the compression in the symptomatic chronic venous disease patients seems to be
also reasonable and unquestioned. The final recommendations for the compression
in PTS prevention should be verified in further clinical studies.
Anticoagulation in PTS prevention
The use of anticoagulation remains the major way of DVT treatment in the acute as
well as follow up phases [8]. In some of the
patients, the minimum DVT anticoagulant treatment (3 months) has to be
prolonged, especially if the risk of DVT recurrence remains significant [8]. Considering the described relationship
between ipsilateral DVT recurrence and higher PTS occurrence, an avoidance of
the thrombosis recurrence in the same extremity seems to be one of the major
goals of the proper management algorithm [1],
[8]. To cope with this, various ways of the
pharmacological treatment based on the evaluation of the benefits and risks of
anticoagulation have been proposed. Most of the anticoagulant treatment studies
in DVT patients focus on venous thrombo-embolism (VTE) recurrence, not on PTS
prevention. Some meta-analyses as well as post-hoc evaluations allow the
conclusion, that there is a potential influence of at least some of the drugs on
a decrease of PTS rate. Comparing the efficacy of the use of oral anticoagulants
from the vitamin K antagonist group with low molecular weight heparin (LMWH),
the latter seem to have a positive influence on PTS rate reduction at least in
some of the performed studies [1], [3], [4]. To
explain these findings both, potential anti-inflammatory as well as the local
thrombolysis stimulating effects of LMWH were suggested [36], [37],
[38], [39], [40]. A retrospective sub-analysis
from the Home-LITE study concerning the patients treated with long term course
of tinzaparin in comparison with standard anticoagulation treatment based on the
short tinzaparin course and warfarin in iliac DVT patients suggests a lower rate
of PTS in tinzaparin group [41]. A
meta-analysis of 5 studies that reported on total vein recanalization after DVT
episodes demonstrated a risk ratio of 0.66 (95 % CI 0.57–0.77; P < 0.0001) in
favor of long-term LMWH [42]
An implementation of the new treatment DVT modalities (including the direct oral
inhibitors of factor Xa and factor II) is an important step towards the safe and
efficacious DVT treatment. Taking into account the still more and more frequent
use of this new therapeutic options in the DVT treatment, the potential
influence of these therapies on the PTS occurrence should also be investigated.
In the post hoc EINSTTEIN DVT/PE study analysis no significant differences in
PTS rate between the standard (warfarin) and rivaroxaban treated patients were
found, if comparable groups were evaluated [43]. Interesting and encouraging results were obtained in a prospective
randomized controlled trial comparing the outcomes of rivaroxaban (61 pts.) or
warfarin (39 pts.) treatment after median follow up of 23 months in the proximal
DVT episode patients. Using the Villalta score assessment, the PTS was diagnosed
in 49 % patients treated with warfarin and in 25 % of the patients treated by
rivaroxaban [P = 0,013, OR for PTS development in warfarin group 2.9 (1.2 –
6.8)] [44]. To get a stronger evidence, the
promising results of this study should be confirmed in larger group studies and
observations.
Open vein concept – local thrombolysis in proximal DVT treatment and PTS
prevention
The “open vein concept” with the early vein lumen patency restoration in the
proximal DVT patients suggests the possibility of the PTS prevention by the
means of the early thrombus removal [45].
Historically, the possibility of the rapid vein lumen restoration in DVT
patients was proven in the patients that underwent venous surgical thrombectomy.
Currently invasive acute proximal DVT treatment, in most of the cases, is
performed as local catheter directed thrombolysis or pharmaco-mechanical methods
[46], [47], [48], [49], [50], [51]. Despite the technical progress in the
procedure performance as well as encouraging reports concerning the prospective
observation of the case series, the efficacy of this treatment modality in term
of PTS prevention remains questionable. In the CAVENT randomized controlled
trial, a reduction of PTS rate of 14.4 % was observed [47]. In this study 209 patients with
ilio-femoral DVT were enrolled and randomized to the groups treated by catheter
directed thrombolysis (CDT) with rtPA administration or to the standard
anticoagulation (189 patients were followed up). In the recently published
ATTRACT trial results, 337 patients were randomized to the local thrombosis
group (CDT or pharmaco-mechanical) and 355 patients to the standard
anticoagulation treatment [51]. In the study
cohort (patients with proximal DVT including also ilio-femoral DVT) the rate of
PTS (assessed by the means of the Villalta score) was 46.7 % in the thrombolysis
arm and 48.2 % in anticoagulation group (p = 0.56) with higher rate of the major
bleedings in the patients treated by thrombolytic treatment (1.7 % vs 0.3 %;
p = 0.049). New published data with further analyses of ATTRACT results,
regarding the group of the patients with DVT limited to the ilio-femoral segment
[52]. In this subpopulation the local
thrombolysis was associated with a reduced rate of moderate and severe PTS
(Villalta > 9) occurrence after 24 months of follow up (thrombolysis: 18 % vs
anticoagulation: 28 %; p = 0.021). Severe PTS (Villalta > 14) in this cohort
was reduced from 15 % in the anticoagulation group to 8.7 % in the thrombolysis
treated patients (p = 0.048).
Open surgical concepts remain for sure an interesting and valid option in the
area of DVT treatment and PTS prevention. However according to the current
research results, the real value of this hypothesis in the PTS prevention has to
be investigated in further research based on the well projected studies with an
implementation of proper and objective PTS criteria. On the other hand, the
invasiveness of a thrombolysis treatment and potential risk of bleeding allows
the clinical application of this treatment approach only in a limited number of
patients.
The successful post –thrombotic syndrome prevention remains still a difficult
clinical problem and unanswered question in many of the research areas.
Despite the presence of several PTS predictive models as well as the
knowledge concerning some of the PTS predictive factors, we are probably
still not able to predict the final outcome of the DVT episode in the
individual deep vein thrombosis patient. Further studies are required with
the urgent need of new, objective PTS criteria and standardized way of PTS
evaluation.
The paper was supported by scientific grant no. KNW-1–185/N/6/K from Medical
Universiy of Silesia Katowice, Poland
