The development of valvular incompetence after deep vein thrombosis: A follow-up study with duplex scanning

Transcription

1 The development of valvular incompetence after deep vein thrombosis: A follow-up study with duplex scanning Bert van Ramshorst, MD, PhD, Paul S. van Bemme1en, MD, PhD, Hans Hoeneve1d, RVT, and Bert C. Eike1boom, MD, PhD, Nieuwegein, The Netherlands Purpose: Duplex ultrasonography with distal cuff deflation was used to establish the physiologic reflux duration in different segments of the deep venous system in healthy individuals, and to document the occurrence of deep vein valve incompetence in patients after deep vein thrombosis (DVT). Methods: Two hundred fifty-two vein segments in 42 legs of21 healthy individuals and 160 deep vein segments in 27 patients with phlebographic ally documented DVT were examined with duplex scanning. Results: The duration of reflux in healthy subjects was significantly shorter in distal deep vein segments. Ninety-five percent of the values were less than 0.88, 0.8, 0.8, 0.28, 0.2, and 0.12 seconds, respectively, for the common femoral, superficial femoral, deep femoral, popliteal, and posterior tibial vein (at midcalf and ankle level). The 95 percentile for reflux duration in the superficial venous system was 0.5 seconds for all vein segments, regardless of the location. No significant correlation was found between the reflux peak flow velocity and reflux duration (R = 0.6). The reflux peak flow velocity is therefore not useful as a parameter of the degree of reflux. The patient group was examined with an interval of 18 to 51 months (mean 34 months) after DVT. Forty-five percent of the initially affected segments showed valve incompetence at follow-up (n = 54); only three of 40 segments initially free from thrombus showed pathologic reflux at follow-up (p < 0.01). Reflux durations in most of the incompetent vein segments were two or more times the normal value of reflux duration. The highest prevalence of valve incompetence was found in the superficial femoral and popliteal vein segment (p < 0.01). None of the patients showed valve incompetence at all levels of the deep venous system. A significant (p = 0.04) relation was found between the extent of the initial thrombosis and the number of refluxing vein segments at follow-up, but no correlation was found between the extent of initial thrombosis and the late clinical symptoms (p = 0.16); clinical symptoms could not be related to the number of incompetent vein segments. Conclusions: Duplex scanning allows a good discrimination between physiologic and abnormal reflux duration and is an important tool in the evaluation of the postthrombotic limb. Early assessment after DVT may have prognostic value in individual patients. (J VAse SURG 1994;:59-66.) The long-term clinical outcome of patients after an episode of deep venous thrombosis (DVT) of the lower extremity is uncertain. Late follow-up has been performed in a limited percentage of patients treated initially, and the results of different studies From the Department of V ascular Surgery, St. Antonius Hospital, Nieuwegein. Reprint requests: Bert van Ramshorst, MD, PhD, Department of Vascular Surgery, St. Antonius Hospital, P.O. Box 2500,3430 EM Nieuwegein, The Netherlands. Copyright 1994 by The Sociery for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter /94/$ /1/52785 are often not comparable because of differences in length of follow-up, patient selection, and treatment. 1 Though early studies report postthrombotic ankle ulceration in as much as 80% of patients at -year follow-up,2,3 in later studies this percentage was found to be as much as 50% and 5%, respectively, at 4 years after DVT, although significant symptoms and venous hemodynamic changes occurred. 4,5 Ambulatory venous pressure measurements are the most accurate physiologic means to grade disease severity, but they reflect total-limb changes and are unable to address the function of individual valves. Noninvasive tests such as pho- 59

2 60 van Ramshorst et at. JOURNAL OF VASCULAR SURGERY Junc 1994 '0 CFV SFV II 0,' I I 1,6 2.' '0 PFV,. 15 PV 0,6 1,1 0,5 1,5 2,5 '0.1 PTVC.. 30.s.0 PTVA to 15 0,' 1, ' 1,5 2,5 Fig. 1. Distribution of reflux duration in healthy volunteers. PFY, Profunda femoris vein. toplethysmography or continuous-wave Doppler similarly lack anatomic selectivity. Ultrasonography duplex scanning has been shown in recent years to be a reliable technique in the diagnosis of venous insufficiency of both the deep and superficial systems. 6,7 The duration of venous reflux can be recorded objectively and under standardized conditions. For the clinical management a clear definition of the physiologic range of reflux duration is fundamental in the assessment of venous dysfunction. In this study we (1) defined the reference values for physiologic reflux duration in different segments of the deep venous system in healthy subjects and (2) investigated the occurrence of deep venous reflux in patients with a previously documented DVT to (a) evaluate the validity of the reflux reference values in a postthrombotic patient population, to (b) document the pattern of distribution of valvular incompetence after DVT, and (c) to define the relationship between severity and level of incompetence and clinical signs of edema and skin changes. MATERIAL AND METHODS Reflux in healthy subjects. The first part of the study comprised the investigation of the physiologic reflux durations and reflux peak flow velocities in healthy volunteers. Both legs in 13 men and eight women (mean age 29.6 ± 6.3 years) were examined. All subjects had no history ofdvt, trauma, surgical procedure, or previous treatment for varicosis in both legs. The 95 percentile value for reflux duration in individual vein segments was chosen as the cutoff point between normal and pathologic reflux and was defined as the normal value for reflux duration (NVR) for that segment. The reflux peak flow velocity was defined in the same manner. Patients. The second part of the study comprised the investigation of deep vein incompetence after thrombosis. Twenty-seven patients (nine men and 18

3 JOURNAL OF VASCULAR SURGERY Volume 19, Number 6 van Ramshorst et at. 61 peak flow velocity em/sec o~ ~ ~ ~ ~ ~ 2 2,5 a a,s 1,5 reflux duration/sec Fig. 2. Correlation between reflux duration and peak flow velocity for all deep vein segments in healthy individuals. R = 0.6; P < women, mean age 49.3 ± 3.8 years) were entered in this part of the study. All patients had a phlebographically documented unilateral DVT and were examined once at a mean of 34 months (range 18 to 51 months) after the initial thrombosis to document the extent of valve incompetence. Fourteen of these patients belonged to a study group in which the rate of thrombus regression after DVT was studied prospectively.9 The extent of thrombosis was stratified according to the number of affected vein segments: calf, popliteal, superficial femoral, deep femoral, and common femoral vein. Three patients had limited iliofemoral thrombosis, patients showed thrombosis in the femoropopliteal segment, in three patients the thrombus was limited to the popliteal-calf area, and in the remaining 11 patients a thrombus was found extending from the calf veins up to the femoral vein. All patients received treatment according to a standard protocol with initial intravenous administration of heparin followed by a maintenance dose of oral coumarin derivates for a period of at least 3 months. The clinical symptoms at follow-up were graded according to the reporting standards in venous disease by the Ad Hoc Committee: class 0, asymptomatic; 1, mild chronic venous insufficiency (CVI); 2, moderate CVI; and 3, severe CVI. Eight patients were graded as class 0, 16 patients were graded as class 1, and three patients were graded as class 2. None of the patients had skin ulceration (class 3). To evaluate whether Table I. Duration of deep vein reflux (in sec) per segment in healthy individuals (n = 42) Segment Modus 75% Value CFV SFV DFV PV PTVC PTVA Table II. Reflux peak. flow velocity (in centimeters per second) per segment in healthy individuals (n = 42) Segment CFV SFV PV PTV Modus 5 75% Value % Value % Value skin ulceration might be associated with more extensive valve incompetence, we also studied seven patients in class 3 (four men and three women, mean age 57.1 ± 17 years) with severe lower limb skin changes and recurrent ulceration after DVT with an interval of9 to 50 years (mean 23.5 years). The site of the initial thrombosis in these patients was unknown.

4 62 van Ramshorst et al. JOURNAL OF VASCULAR SURGERY June 1994 CFV SFV I, 1 0,5 1,5 2,5 Ilme/.. e ;,[ [ 0 0 0,5 r tlme/.. e 1,5 2 2,5 PFV PV 5 -, I I I 0,5 1,5 2,5 tlme/.. c 2 0 II j 0 0,5 r 1,5 IIme/HC 2 2,5 PTVC PTVA tlme/mc 2,5 Fig. 3. Reflux duration per segment in patients after thrombosis. Vertical bars represent cutoff point between normal and pathologic reflux durations; bars to left of cutoff represent normal reflux duration, bars to right of cutoff represent pathologic reflux duration. Table III. Relation between reflux and previous thrombosis Refiux+ Refiux- Previous thrombosis Chi-squared test,p < Previous thrombosis Total Duplex examination. Both healthy volunteers and patients were examined in the standing position with the weight supported by the contralateral leg. Venous reflux and/or peak flow velocities were measured with an ATL Ultramark 4 duplex scanner (Advanced Technology Laboratories, Bothell, Wash,) with release of a pneumatic cuff at six levels of th~ leg by a technique described elsewhere. 9 Venous segments studied included the common femoral vein (CFV), the deep femoral vein (DFV), and the superficial femoral vein (SFV) at thigh level, at knee level the popliteal vein (PV), at calf level the posterior tibial vein (PTVC), and at ankle level the posterior tibial vein (PTV A). No hemodynamic measurements relevant for obstruction or classification of reflux such as ambulatory venous pressure were made in the patient groups.

5 JOURNAL OF V ASeULAR SURGERY Volume 19, Number 6 van Ramshorst et at. 63 Table IV. Distribution of pathologic reflux according to the initial extent of thrombosis Number of deep segments initially affected Number of segments with reflux Total Total Normal value of reflux duration: common femoral vein = 0.9 seconds; superficial femoral vein = 0.8 seconds; DFV = 0.8 seconds; popliteal vein = 0.3 seconds; posterior tibial vein (calf) = 0.2 seconds; posterior tibial vein (ankle) = 0.12 seconds. Statistical analysis. The correlation between peak flow velocity and reflux duration in healthy subjects was made with linear regression analysis. The relation between thrombosis and reflux and the differences between segments were evaluated with logistic regression and chi-square analysis. The relation between reflux and symptoms was calculated with the Wilcoxon two-sample rank test (Mann-Whitney test). Significance was defined as p < RESULTS Normal values for reflux duration. The NVR in healthy volunteers ranged from 0.9 seconds in the CFV to 0.12 seconds in the calf veins (Table I), thus showing a marked difference in reflux duration between proximal and distal deep vein segments, with uniform short reflux periods in distal segments. The distribution of reflux duration per segment (Fig. 1) showed a wide range in the SFV compared with the other segments. Isolated reflux durations of more than 2 seconds were recorded only once in the CFV and SFV. Table II shows the reflux peak flow velocities for different segments. No correlation was found between reflux peak flow velocity and reflux duration per individual segment, nor for all segments together (Fig. 2). Reflux in postthrombotic limbs. The distribution of reflux duration in various segments in patients after thrombosis is shown in Fig. 3. The curves for the SFV, PV, and PTVC show two peaks, indicating a clear distinction between normal and pathologic reflux. Because of the small numbers this effect is not shown for the CFV, DFV, and PTVA. More than 85% of the pathologic reflux durations were two or more times the NVR. Table V. Mean number of segments with reflux according to the extent of thrombosis at diagnosis No. of initially affected segments Mann-Whitney,p = 0.04 N Mean no. of segments with reflux Distribution of deep vein valve incompetence. Of 160 vein segments examined, 1 segments had shown thrombosis previously. Residual occlusion was found in only one superficial femoral vein segment after femoropopliteal thrombosis; in all other affected segments recanalization had occurred. Reflux was documented in 57 segments (Table III); 45% of those segments initially affected by thrombosis showed reflux (n = 54), whereas 66 segments that had shown thrombosis had no reflux. Only three of 40 segments initially free of thrombus were found to have reflux at follow-up (p < 0.01). Reflux in unaffected segments was observed once in the DFV and twice in the PVT segment. The distribution of valve incompetence after thrombosis is depicted in Table IV. Six patients in our study had thrombosis limited to three segments or less; three patients with limited femoral thrombosis and three patients with thrombosis limited to the popliteal/calf area. In four of these patients no deep vein reflux was observed. Initial extensive thrombosis, however, was associated with multisegment reflux (Table V). These differences were significant (p = 0.04), although in

6 64 van Ramshorst et al. JOURNAL OF VASCULAR SURGERY June 1994 Table VI. Prevalence of reflux at different levels after thrombosis Vein segment No. of segments affected by thrombosis No. of segments with reflux Percent CFV DFV SFV PV PTVC PTVA Mann Whitney,p < none of the patients extensive thrombosis resulted in incompetence at all levels of the deep venous system. The prevalence of reflux at different levels after thrombosis is shown in Table VI. The rates for the various segments were not similar, and the SPV and the popliteal vein segment scored significantly more reflux than the other vein segments (p < 0.01). Symptoms related to reflux. No correlation was found between late symptoms and the initial extent of the thrombosis (p = 0.16). None of the clinical symptoms such as pain, edema, or trophic skin changes showed any relation to the number of incompetent vein segments. The patients in the study group, however, had fewer incompetent segments (2.2 ± 1.1, mean ± SD) compared with the patients with skin ulceration who were also studied (3.6 ± 0.5). This difference was significant (p = 0.005). DISCUSSION In the first part of our study the physiologic range of reflux duration in different vein segments of the lower extremity in healthy individuals was clearly defined and showed a significant difference between proximal and distal vein segments with uniform short reflux duration in distal segments. Because reflux is the result of gravity, venous valve insufficiency testing with duplex scanning should be performed with the patient in the standing position. Pressure studies have shown that valves refluxing with the patient in erect position may show competence with the patient in the supine position, and this was confirmed in a recent duplex study. The rapid cuff-deflation technique used in our study to elicit reflux at different levels provides a standardized reflux provocation that has distinct advantages over other techniques like manual compression and the valsalva maneuver, as shown previously.ll Our study is a further refinement of the observations of Van Benimelen et al.,9 who defined a 95 percentile of 0.5 seconds for reflux in healthy subjects. This value was derived from the examination of 32 legs, but no clear distinction was made between different segments. Valve closure results from a retrograde flow that is elicited by a reversed transvalvular pressure gradient. This pressure gradient is composed of the negative pressure occurring after cuff release and the gravitational forces of the blood column proximal to the valve. The pressure gradient cannot be measured directly, but we can measure the blood flow velocity instead. The smaller blood columns being displaced in distal segments after cuff deflation should result in lower pressure gradients (i.e., lower peak flow velocities in these segments). This was not observed in our study. With the exception of the superficial femoral vein, the range of peak flow velocities in the different segments were very similar, with most segments showing a peak flow velocity of cm/sec or less. Because no correlation was found between reflux peak flow velocity and reflux duration, peak flow velocity is not a useful measure of the degree of reflux. The profound effect of thrombosis on the venous valves has been well known since it was first described by Edwards and Edwards in As shown in the second part of our study, destruction of the valves leads to pathologic reflux durations that, in most of the incompetent deep vein segments under study, were two or ll).ore times the NVR. These findings confirm that duplex scanning allows an easy classification of venous reflux as either normal or pathologic. The symptoms of the postthrombotic syndrome such as pain, edema, hyperpigmentation, and ulceration are commonly attributed to valve incompetence resulting in venous hypertension. Valve incompetence is reported in the literature at sites removed from the initial thrombus in patients with iliofemoral thrombosis,4,13 and controversy exists whether valve incompetence is the result of direct

7 JOURNAL OF VASCULAR SURGERY Volume 19, Number 6 van Ramshorst et ai. 65 damage to the valves caused by the inflammatory process after thrombosis or, in a number of patients, is secondary to residual proximal obstruction and venous hypertension with subsequent overdistension and distraction of the valve cusps. The findings of our study, with valve incompetence almost exclusively confined to previously affected segments, strongly support the "direct damage" theory. In several studies 8,14,15 thrombus propagation has been reported despite adequate treatment. The incompetence in three segments without initial documented thrombosis may be the result of unnoticed thrombus propagation and may therefore still be postthrombotic in origin. Of the initially affected segments, 66 (55%) did not show reflux at follow-up. Residual obstruction was found in only one segment, and our findings suggest that thrombus regression in the remaining 65 segments left the valvular structures undamaged. The patients in our study were examined on only one occasion at a relative short interval after thrombosis, and although the study describes neither the progression of symptoms nor reflux changes over time, the results indicate that significant damage to the valves occurs after DVT, which was, however, not yet reflected in the relatively benign symptoms. In our patients thrombosis limited to three segments or less in either proximal or distal segments was associated with minor hemodynamic sequelae. Extensive thrombosis was followed by more severe hemodynamic abnormalities (Table Ill). These findings are in agreement with those of Browse et al.,16 Widmer et al.,17 and Lindner et al.,18 who reported a higher prevalence of postthrombotic sequelae in patients with severe thrombosis than in those with minor thrombosis. The higher prevalence of postthrombotic valve incompetence in the SFV and PV compared with that of the other segments has not been reported previously. Because thrombus regression was shown to proceed at an equal rate in all deep vein segments of the upper leg, 8 an apparently higher initial thrombus load in the SFV and PV segment leads to more residual thrombus and a higher incidence of valve damage in these segments. Although no patients with isolated calf vein thrombosis were entered in our series, less valve damage was observed in the calf vein segment. It is unclear whether this is a result of a lower thrombus load in the small-caliber calf veins or reflects a faster and more complete thrombolysis as suggested by Lea Thomas, resulting in less valve damage. The lower prevalence of valve insufficiency observed in the calf region in our series casts doubt on the important role attributed to calf vein thrombosis in the development of the postthrombotic sequelae as reported in the literature. 21,22 No attempt was made in our study to assess the influence of the age of the thrombus on the development of late valve incompetence. Most of the patients with a short- to mediumterm follow-up had edema or trophic skin changes, but the disease severity, in terms of the number and location of incompetent vein segments, could be predicted by neither clinical examination nor the subjective complaints of the patients. These findings confirm an earlier study by Kakkar, 19 who reported a poor correlation between clinical symptoms and hemodynamic status. In patients with a long interval since DVT, recurrent skin ulceration was associated with more severe valve incompetence. Because no ulceration was found yet in our patients with short-term follow-up, a longer time interval is apparently necessary for severe symptoms like ulceration to develop. Whether ulceration is the result of progressive hemodynamic deterioration in patients with mild insufficiency after DVT or the late effect of long-standing severe multisegment incompetence is unclear. Eleven patients without ulceration showed incompetence at three or more levels with duplex scanning. Further study may reveal whether these patients with more extensive valve incompetence are at special risk of experiencing ulceration over time. The current anticoagulant therapy in acute DVT is ineffective in preserving normal venous valve function. Venous thrombectomy in selected patients may result in a superior outcome, as reported by Neglen and EkloF3 in a nonrandomized series, but is, like thrombolysis, traditionally associated with a high recurrent thrombosis rate and incidence of postthrombotic problems. 19,24,25 Postthrombotic venous insufficiency therefore will continue to be a significant clinical problem. The follow-up of patients with DVT should be directed at the detection of hemodynamic deterioration in the affected limb before symptoms develop. Patients at risk should be identified, and the effect of early preventive measures such as elastic compression stockings or specific surgical therapy should be evaluated. In this way chronic disability may be avoided. Duplex scanning will be an important tool in the noninvasive hemodynamic assessment of the postthrombotic limb, because the disease severity and site of incompetence can readily be identified.

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