The effect of recanalization of venous thrombi on valve function

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The effect of recanalization of venous thrombi on valve function

Mark H Meissner University of Washington. Seattle. Washington. USA

Introduction

Manifestations of the post-thrombotic syndrome, including pain, oedema, hyperpigmentation and ulceration, have been recognized to occur in as many as two-thirds of patients following an episode of acute deep venous thrombosis (DVT).I With approximately 250000 individuals per year sustaining an acute DVT in the USA,2 a significant number of patients are at risk for post-thrombotic sequelae. In the UK, leg ulcers have been reported to have a prevalence of0.18%

of the population and 0.38% in those under age 40 years.' Coon et al? estimated an age-adjusted prevalence of stasis changes and ulcers in the USA of 5%. This corresponds to six to seven million individuals with stasis changes and 400 000 to 500 000 with leg ulcers. Similarly, a 3% prevalence of pronounced chronic venous disease has been reported among Swiss adults;" 10% of these patients were unable to work and 90% required medical treatment. Chronic venous insufficiency ranks fourteenth among diseases causing tempo- rary absence from work and thirty-second among causes of permanent disability in BraziJ.5

Among high-risk groups, prevention of DVT

Address for correspondence: Mark H Meissner, Department of Surgery, ZA-16, Harborview Medical Center, 325 9th Avenue, Seattle, WA 98104, USA.

©Edward Arnold 1995

is the most appropriate measure for preventing post-thrombotic disease. However, once an episode of DVT has occurred, few measures other than adequate anticoagulation and compression stockings exist to minimize post-thrombotic sequelae. This is in part related to an incomplete understanding of the aetiological mechanisms of deep venous insufficiency. Not all patients manifest the signs and symptoms of the post-thrombotic syndrome after an episode of acute DVr, and the determinants of this syndrome remain unclear. An understanding of what factors contribute to the development of the post-thrombotic syndrome in some patients, but not in others, may provide insight into minimizing its occurrence.

Natural history of acute deep venous thrombosis

Recanalization after deep venous thrombosis Edwards and Edwards> noted in 1937 that thrombi produced by sodium morrhuate injection recanalized to produce a patent but valveless lumen. However, determination of the frequency and rate of recanalization in spontaneously occurring thrombi was not possible until the development of noninvasive technology permitting serial examination of patients. Duplex

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ultrasonography has proven ideal in this regard, permitting precise localization of thrombi to specific venous segments, serial examination of involved segments, and documentation of the development of valvular reflux. Using duplex ultrasound, Killewich et al.! demonstrated that recanalization, or 'spontaneous lysis', occurred early in the natural history of acute DVT, although with considerable individual variation.

Among 21 patients studied, 44% showed some evidence of recanalization by seven days. At least some involved segments had recanalized by 90 days in all patients, with recanalization of all involved segments in 53% (Figure 1). Similarly, among 123 extremities with DVT, Markel et al»

noted that all involved common femoral, popliteal and posterior tibial veins had recanalized by one year, while only two superficial femoral vein segments remained occluded,

The events leading to re-establishment of the venous lumen, variously referred to as recanalization or spontaneous lysis, are a com- plex series of events involving both cellular and biochemical processes. The pathological events beginning with the formation of thrombi in the valve sinuses and culminating in recanalization have been reported in detail by SevittY-12 Throm- bus organization originates from the point of attachment to the vein wall and involves thrombus

retraction and peripheral fragmentation induced by surfacing cells derived from the vascular endothelium. This is accompanied by fibrinolysis occurring both at the periphery and from within the thrombus.I I Complete recanalization produces a restored lumen with fibroelastic inti- mal thickening at the point of original thrombus attachment.

Valvular reflux

Venous hypertension is generally accepted as the haemodynamic mechanism underlying the manifestations of the post-thrombotic syndrome.P However; venous hypertension could theoretically arise by several different mechanisms: persistent proximal venous obstruction, diversion of blood through high-resistance venous collaterals, or valvular imcompetcnce.t- Although anomalies of venous outflow do exist following deep venous thrombosis,14,15 the clinical manifestations of the post-thrombotic syndrome appear to be primarily due to valvular incompetence rather than to residual venous obstruction. Persistent venous obstruction is more commonly associated with venous claudication. Given the frequency and rapidity of venous recanalization, it is not surprising that persistent obstruction is unusual among patients with the post-thrombotic syndrome.!o Killewich

100

80

60

'l(,or PaUlnl.

w"h ₄₀ Ly.l.0' ThrombI

20

(0121) 0

0 30

(17117)

110

DiY' (15115)

180

(919)

270

Figure 1 Rate of recanalization among 21 patients followed with serial ultrasonography. Percentage of patients with lysis in any originally occluded segment. Number of patients with lysis compared with number studied in parentheses. (Reproduced with permission from Killewich LA Bedford GR, Beach KW, Strandness DE. Spontaneous lysis of deep venous thrombi: rate and outcome.

J VascSurg1989; 9: 89-97.)

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et a/.¹⁵ noted that, although venous outflow as determined by strain gauge plethysmography was diminished following an acute DVT, this did not correlate with development of the post- thrombotic syndrome. In contrast, a reduction in venous refilling time, suggestive of valvular incompetence, was significantly associated with post-thrombotic disease. The association of valvular incompetence with venous hypertension and the post-thrombotic syndrome has been con- firmed by several other investigators.17-19

The mechanism by which valvular insufficiency develops following recanalization remains an important question. Edwards and Edwards>

noted that recanalization of thrombi produced by sodium morrhuate injection resulted in valvular destruction. Clinically, Budd et al.²⁰ noted thrombus fusing the leaflet to the valve sinus with erosion or obliteration of both the endothelium and basement membrane in 50% of patients undergoing valve transplantation for established venous insufficiency. Cases without residual thrombus demonstrated endothelial erosion with thickening of the basement membrane. However, such valvular destruction does not appear to be a universal consequence of acute DVT. When followed with duplex ultrasound, only 33-59%

of involved venous segments have been noted to develop reflux at one year." .

The histological changes accornpanymg acute DVT provide some insight into the mechanisms underlying valve preservation in some patients.

In contrast to the observations in patients with established post-thrombotic syndrome, Sevitt^ll^{, 12} has noted that the fibrocellular organization following acute DVr rarely involves the valve cusps.

Attachment of thrombus to the valve cusps was noted in only four of 44 specimens examined. In the majority of cases, the thrombus was found to be separated from the valve cusp by a cleft.'? Such lytic clefts were postulated to arise from the local fibrinolytic activity of the valvular endothelium.

These observations are consistent with the intense plasminogen activator activity known to be associated with the venous valve CUSpS.21 The valve cusps may thus be protected from the destructive processes accompanying recanlization, recovering normal function once complete recanalization has occurred.

As shown in Figure 2, the development of reflux occurs shortly before or simultaneously

with complete recanalization.P Deterioration of normal valve function is rarely observed once complete recanalization occurs. However, transient reflux can occasionally be observed in partially recanalized veins. Such transient reflux resolves after complete recanalization and presumably occurs when otherwise normal valve cusps remain partially encumbered with residual thrombus. This phenomenon is consistent with the protective effect of the lytic clefts described bySevitt.»

The post-thrombotic syndrome

Development of the clinical manifestations of the post-thrombotic syndrome appears to depend upon at least two factors, In addition to the pres- ence or absence of valvular reflux, the anatomical sites of reflux appear to be important determinants of clinical signs and symptoms. Gooley and Sumner'? found that abnormal venous refilling times were determined primarily by incompetence of the distal deep and superficial venous systems.

Clinical sequelae were also strongly associated with caudal deep venous incompetence, again with some contribution from superficial venous incompetence. Only 7% of the postphlcbitic limbs in their series had neither superficial nor deep venous incompetence. Rosfors et al.v' found the highest incidence of severe disease among those with both posterior tibial and popliteal vein incompetence. Van Bemmelen et al.t" found incompetence of the greater and lesser saphenous veins and the posterior tibial veins to be significantly associated with ulceration. They further postulated incompetent perforating veins to playa role in those cases with superficial venous incompetence.

In contrast to studies associating clinical symptoms with the sites of reflux, little is known about why some valves remain protected during the processes of thrombus formation and recanalization, while others are rendered incompetent. Such differences are observed both between individuals with DVT as well as between segments of the lower extremity veins. Some lower extremity venous segments, particularly the posterior tibial veins, appear to be more resistant to the development of valvular insufficiency. A significantly smaller number of involved posterior tibial win segments develop reflux in comparison to other venous segments.^H,22Such observations have been

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attributed both to the large number of valves in this segment and the increased efficiency of thrombus fragmentation in small veins.!2 Differ- ential susceptibility to valvular injury between individuals is more difficult to explain. Poten- tial mechanisms could include differences in rates of recanalization, individual differences in fibrinolytic activity, and the effects of recurrent thrombosis and extension of the initial thrombus.

Determinants of valvular incompetence Early recanalization

The potential benefit of early recanalization in preserving valvular function has been the ration- ale for using thrombolytic therapy in deep venous thrombosisP-25 Indeed, the use of thrombolytic therapy would seem to be an ideal model for examining the effect of rapid recanalization on preservation of valve function. Thrombolytic

therapy has been reported to produce at least some degree of lysis in 53-70% of cases,24.26-JO although no single study of thrombolytic therapy has had sufficient power to prove its efficacy in comparison with standard anticoagulant therapy." In a pooled analysis of six trials deemed to have appropriate randomization, Goldhaber et al.^J2 concluded that streptokinase was 3.7 times more likely to produce some degree of thrombolysis than was heparin (p

<

0.00(1). However, what implication this has for long-term venous function is somewhat less clear as thrombolysis was defined as 'greater than minimal phlebographic evidence for dissolu- tion of clot'. Several investigators have reported partial thrombolysis in 20-25% of cases,24.2R-JO accounting for approximately one-third of the cases with greater than minimal thrombolysis.

It would seem doubtful that anything less than complete thrombolysis would be effective in preserving valvular function.

PlV GSV PPV 8Aol SfO

SEGMENT eN SFP

700

eoo

* *

!IOO

~400-<

Q 300

200

100

Figure 2 Median time to complete recanalization in comparison to the median time to development of reflux in segments ultimately developing reflux. Lysis and reflux times are not significantly different with the exception of the SFM and SFD segments(*p«:0.05). Segments:

common femoral vein (CFV), proximal superficial femoral vein ISFP), mid superficial femoral vein (SFM), distal superficial femoral vein (SFD), popliteal vein (PPV), posterior tibial vein (PTV).profunda femoris vein (PFV)and greater saphenous vein (GSVj. (Reproduced with permission from Meissner MH, Manzo RA, Bergelin BO, MarkelA.Strandness DE. Deep venous insufficiency: the relationship between lysis and subsequent reflux JVase Surg1993;18:596-608.)

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Valvular function could, however, be theoretically preserved in the 37-61% of patients achieving complete thrombolysis,24,28--3o.33 Unfor- tunately, studies providing long-term follow-up of these patients have been limited, Of the ninest~d

ies providing follow-up of patients treated with thrombolytic therapy, seven suggested successful preservation of valve function,23,25,2/!.3o,34-36 one report was ncgativc.?" and one was inconclusive.F However, studies reporting beneficial effects with thrombolytic therapy have had small numbers of patients and have included patients with both complete and partial thrombolysis. Three of the studies lack control groups25,2/!.37 and only three report follow-up beyond two years. 25,36,37 It is clear, however, that follow-up phlebograms are frequently abnormal, with residual abnormalities reported in 57-100% of cases,23.2/!.35-,37 ,

Physiological tests of venous function following thrombolytic therapy have been equally difficult to interpret. Using plethysmography, Johansson et a/,2/! demonstrated findings consistent with reflux in only two of 19 patients. Similarly, Norgren and Widrncr-" observed that foot volumetry is relatively normal if complete thrombolysis can be achieved. In contrast, Albrcchtsson et a/,37 reported foot volumetry findings consistent with deep venous insufficiency in 26 of 36 extremities (72%)treated with streptokinase, Similarly, Kakkar and Lawrence-"

concluded that foot volumetrywas not improved following thrombolytic therapy, irrespective of the degree of thrombolysis. Correlation of the results with clinical findings has also been vari- able. Sieger eta/.2.1 reported no post-thrombotic symptoms at 12 months among patients treated with streptokinase. Common et a/.³⁵ reported symptoms in only five of 15 patients following streptokinase versus six of 12 patients treated with heparin. Only symptoms of oedema were reported in the streptokinase group, while one ulcer developed in the heparin group. Arnesen et a/.³⁶ reported postphlebitic signs in four of 17 patients treated with streptokinase versus 12 of 18 patients treated with heparin, three of whom developed ulvers. In contrast, Albrechtsson et a/.J7found only 26% of 35 patients to be free of post-thrombotic signs or symptoms, with skin changes occurring in 17% at an average follow-up of29months.

In summary, the ability of thrombolytic therapy

to restore an anatomically normal deep venous system early following DVT is well documented in at least some cases. This theroretically should contribute to the preservation of valvular function and a decreased incidence of the post- thrombotic syndrome. Unfortunately, long-term follow-up of these patients has been limited and is unable to conclusively establish a benefit of early thrombolysis.

We have, however, identified early recanalization as an important determinant of the eventual development of reflux among patients not treated with thrombolytic therapy, Serial duplex ultrasonography was used to follow recanalization and the development of reflux in 123 extremities (113 patients) followed from the time of presentation to complete lysis,22 The lower extremity venous system was divided into eight segments that were examined at intervals of one day, seven days, one month and every three months for the first year following an acute DVT, Patients were evaluated at yearly intervals following the first year. The time to complete recanalization was then related to the eventual development of reflux. Average follow-up for the entire group was 17.6 (standard deviation

±

15.3) months. In comparison to segments developing reflux, complete recanalization occurred more rapidly in segments not developing reflux, Depending upon the segment, recanalization took 2.3 to 7.3 times longer in veins developing reflux. This was noted in all segments except the posterior tibial vein, in which the time to complete recanalization was nearly identical among those developing and not developing reflux (Figure 3, Table 1).This difference was statistically significant (p < 0.05) for the midsuperficial femoral, popliteal and profunda veins.

The time to complete recanalization thus docs appear to be an important determinant of valvular incompetence in all segments except the posterior tibial vein. However, it is notable that a few

se~ments eventually develop reflux despite early lySIS (less than one month) while other segments appear to be protected from reflux despite relatively late lysis (more than nine months). This suggests that other factors may be operative in these segments as well as in the posterior tibial vein.

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Deficiencies of fibrinolysis

Despite the importance of time to recanalization, it is not the sole determinant of the eventual development of reflux. Individ- ual differences in the fibrinolytic system may be particularly important in this regard. Fibrinolytic

deficiencies among patients with acute OVf have been reported by several investigators.w-"

Not surprisingly, in addition to congenital plasminogen deficiencies and abnormal fibrino- gen variants, abnormalities of both tissue type plasminogen activator (tPA) and plasminogen

"'+-- -+---+-+--+-- -+-- -+---1 ^• ^REFlUX

~ NOREFLUX

- +-- -+-- -+-+--+-- -+-- - + - - - +- - +---i

prv GSV PTV

SJ'D PPV SEGMENT 100

~ sot+-+-_ .+---+-+--+-- -+---+--- +- -4-- --i

~~ ⁴⁰¹+-+-ji-+--+

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Figure 3 Mediantimefrom thrombosisto complete recanalization,grouped accordingto ultimatereflux status. Error bars denoteinterquartile range.

Segments:common femoral vein(CFV). proximalsuperficial femoralvein (SFP). midsuperficial femoral vein(SFM),distalsuperficialfemoral vein (SFD),poplitealvein(PPV), posterior tibialvein(PlY),profunda femoris vein (PFV)and greater saphenous vein(GSV).(Reproduced with permissionfrom Meissner MH,Manzo RA. BergelinBO,MarkelA,Strandness DE.Deep venous insufficiency:the relationshipbetween lysisand subsequent reflux.J Vase Surg1993;18:596-608.)

Table 1 Lysis time and venous reflux

Segment Reflux No reflux

n Lysistlme- 10 ranqe> n Lysis time- 10range^b

Common femoral 10 279 104-577 14 111 37-208

ProximalSFV 15 214 95-474 18 73 30--245

MidSFV 10 474 245-736 16 65 15-199

DistalSFV 7 268 230-433 13 118 34-371

Popliteal 10 260 187-388 20 93 29-190

Posteriortibial 8 72 49-130 38 80 28-182

Profunda 5 375 289-388 10 130 30-275

Greater saphenous 6 287 145-348 7 98 4-191

p

0.14 0.086 0.002 0.15 0.006 0.85 0.04 0.11

• Medianlysistimein days

bInterquartilerange, 25th to 75th percentile

Reproduced withpermissionfrom MeissnerMH,Manzo RA, BergelinBO,Markel A, Strandness DE.Deep venous insuffi ciency: the relationsh ipbetween lysisand subsequent reflux.JVase Surg1993;18:596-608.

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activator inhibitor (PAl) generation have been implicated.>" Juhan-Vague et al.:\!" found an abnormal fibrinolytic response among 37% of 120patients with idiopathic or recurrent DVT.

Of these patients, approximately one-quarter had increased levels of PAl while three-quarters had diminished tP A release in response to venous occlusion. Prins and Hirsh.?" as weIl as Francis.>"

have criticaIly reviewed the literature regarding abnormal fibrinolysis and acute DVT. Both agree that the data concerning idiopathic DVT and fibrinolytic deficiency are currently inconclusive, although there docs appear to be a clear relationship between postoperative DVT and elevated levels of PAl.

Disordered fibrinolysis could similarly influence the eventual development of valvular reflux and chronic venous insufficiency. Impaired inter- stitial fibrinolysis has been implicated in formation of the pericapiIlary fibrin cuff observed in lipodermosclerotic skin.:" It is conceivable that impaired intravascular fibrinolysis also has a role in the development of valvular insufficiency. Intravascular fibrinolysis can be thought of as proceeding through both intrinsic and extrinsic pathways.P Intrinsic fibrinolysis involves fibrinolytic agents incorporated into the thrombus during formation, while extrinsic fibrinolysis occurs through either circulating or locally released agents. Both mechanisms have potential implications for the development of reflux.

Deranged intrinsic fibrinolysis could affect the eventual development of valvular incompetence through prolongation of lysis times as weIl as a tendency toward recurrent thrombosis or thrombus extension. A relationship between deficient tPA release and recurrent venous thrombosis has been noted by some investigators.P' In contrast, extrinsic fibrinolysis may be responsible for pro- tection of the valve cusps, with damage resulting from impaired local fibrinolysis. Endothelial cells are known to elaborate both tissue-type and urokinase-type plasminogen activators, as well as PAI.43 Endothelial fibrinolytic activity appears to be particularly intense at the valve CUSpS,21 where the balanced interaction of activators and inhibi- tors may be particularly important. Sevitt's't-'?

observation of lytic clefts around the valve cusps suggests that this balance usually prevents initial thrombus adherence and subsequent fibrocellular organization. Derangements in the local balance

between tPA and PAl could conceivably result in the rare cares of thrombus adhesion to the valve cusps. Such cases presumably correspond to those with eventual endothelial and basement membrane erosion described by Budd et al. in patients with valvular insufficieny.?"

Thrombus extension and recurrence

The importance of recurrent thrombosis and thrombus extension also warrant consideration as contributing factors to the development of reflux. Recanalization appears to be a dynamic process, with lysis and rethrombosis occurring as competing events early after an acute DVr.

During the follow-up of 113 patients, W-2W/r' of segments studied were noted to develop rethrombosis prior to complete recanalization.F Such figures may underestimate the true occurrence of this phenomenon, as patients were examined only seven times during the first year after DVT. Although too small for statistical analysis, the incidence of reflux appeared to be higher in such patients. Dhall et al.⁴⁴ similarly noted that rethrombosis was problematic among patients achieving only partial thrombolysis with streptokinase, occurring in 18of30patients in this setting.

Extension of thrombus to adjacent segments may also have implications for the development of reflux. Among patients at our institution, extension of thrombus to adjacent segments may occur in up to one-fourth of patients (unpublished data). Krupskietal.^4shave similarly found extension of thrombus in 38% of patients followed by duplex ultrasonography, despite adequate anticoagulation in two-thirds. As the total number of segments involved almost certainly affects the time to complete lysis, valvular injury may be more likely in such patients. Although data for spontaneous recanalization are lacking, the efficacy of thrombolytic therapy does appear to be related to the extent of thrombus.v'-s«

The relationship between intensity and dura- tio~of anticoagulation and recurrence and propagation of thrombus is unknown at present."?

Both phenomena can occur despite apparently adequate anticoagulation." However, it is not known at what point during recanalization the risk of rethrombosis decreases or if prolonging anticoagulant therapy reduces this risk. In a small study with short follow-up, Schulman et al, reported no

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difference in the incidence of signs or symptoms of venous insufficiency between patients treated with anticoagulation for four weeks or three months.sf However, in a much larger study, clinical recurrence of DVT and pulmonary embo- lus was shown to be lower following three months of anticoagulation in comparison to an abbrevi- ated four-week course.w Unfortunately, no study has documented the relationship between recurrence and duration of therapy using serial duplex ultrasonography. For the present, the relationship between the duration of anticoagulation and post- thrombotic sequelae remains unknown.

Clinical implications

Although many of the determinants of venous insufficiency after DVT remain unclear, there may be some clinical applications from our knowledge to date. Early recanalization does appear to be important in preserving valvular integrity in all except the tibial segments. Thrombolytic therapy may thus have a role in thrombi not involving the calf veins. However, to be effective such treatment must result in complete recanalization.

Furthermore, since initial thrombus adherence to the valve cusp may determine the eventual development of reflux, the prevention of reflux would seem more likely if therapy was instituted soon after DVT. Unfortunately, many patients with DVT have contrainindications to thrombolytic therapy. In our institution, only 7%

of patients with an acute DVT are candidates for thrombolytic therapy.50

Among patients treated with standard anticoagulation measures, compression stockings are routinely recommended to minimize the effects of venous hypertension. Although appropriate in the majority of patients, it may be possible to predict patients at risk for the post-thrombotic syndrome early after DVT. As late development of reflux is rare, those without reflux once complete recanalization has occurred are likely to be at low risk for post-thrombotic sequelae. Such patients may potentially be spared the expense and inconvenience of long-term compression therapy.

Conclusion

The post-thrombotic syndrome continues to be a source of significant morbidity and socioeconomic expense world-wide. Although we currently have some understanding of the physiological process of recanalization and the haemodynamic aberra- tions resulting in valvular reflux, our knowledge is incomplete. In particular, few modalities other than standard compression therapy exist to prevent the development of post-thrombotic symptoms. Identification of the factors that cause the post-thrombotic syndrome to develop in some patients, but not others, may have some role in minimizing the occurrence of this disease. Minimizing the interval to complete recanalization appears to be important in segments other than the posterior tibial veins.

Thrombolytic therapy probably does have a role in this regard, although this is likely only if complete thrombolysis is achieved and has not been conclusively demonstrated. Other factors are also likely to be important although they have not been well studied in the setting of chronic venous disease. Individual differences in fibrinolytic activity clearly have some role in predisposing to acute DVT. A similar role in chronic venous insufficiency is likely, although further work needs to be done in this area.

The potentially important impact of thrombus recurrence and extension also needs further study and may influence the duration and intensity of anticoagulation.

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