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174 Chapter 16 Computed tomography and MRI in venous disease
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43. Kluge A., Mueller C., Strunk J., etal. Experience in 207 combined MRI examinations
for acute pulmonary embolism and deep
vein thrombosis. AJR Am J Roentgenol
2006;186:1686–1696.
44. Dick E.A., Burnett C., Anstee A., etal.
Time-resolved imaging of contrast kinetics
three-dimensional magnetic resonance venography in patients with pelvic congestion
syndrome. Br J Radiol 2010;83:882–887.
45. Lim R.P., Bruno M., Rosenkrantz A.B.,
etal. Comparison of blood pool and extracellular gadolinium chelate for functional
MRevaluation of vascular thoracic outlet
syndrome. Eur J Radiol 2014;83:
1209–1215.
46. Furuta A., Isoda H., Yamashita R.,
etal. Non-contrast-enhanced MR
portography with balanced steady-state
free-precession sequence and time-spatial
labeling inversion pulses: Comparison
of imaging with ow-in and owout methods. J Magn Reson Imaging
2014;40:583–587.
47. Shimada K., Isoda H., Okada T., etal.
Unenhanced MRportography with a
half-Fourier fast spin-echo sequence and
time-space labeling inversion pulses:
Preliminary results. AJR Am J Roentgenol
2009;193:106–112.
PART
Management of acute
https://t.me/med1917
thrombosis
Edited by Thomas W. Wakefield
17 The clinical presentation and natural history of acute deep venous thrombosis
Jake F. Hemingway and Mark H. Meissner
18 Diagnostic algorithms for acute deep venous thrombosis and pulmonary embolism
Joann M. Lohr
19 Medical treatment of acute deep vein thrombosis and pulmonary embolism
Henry Han and Geoffrey D. Barnes
20 Catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis
Brian G. DeRubertis and Rowza T. Rumma
21 Percutaneous mechanical thrombectomy for treatment of acute iliofemoral deep vein thrombosis
Kayla J. Krause, Ahsan Zil-E-Ali, Faisal Aziz, and Peter Gloviczki
3
22 Open and hybrid surgical interventions for the treatment of acute iliofemoral deep vein thrombosis
Ahsan Zil-E-Ali, Kayla J. Krause, Faisal Aziz, and Peter Gloviczki
23 Endovascular and surgical management of acute pulmonary embolism
Armin Farazdaghi and Randall R. DeMartino
24 Treatment algorithms for acute venous thromboembolism
Salim G. Habib and Rabih A. Chaer
25 Prevention of deep venous thrombosis
Jeffrey J. Siracuse and David McAneny
26 Management of venous thoracic outlet syndrome
Chandu Vemuri
27 Acute central venous thrombosis in the setting of central lines, pacemaker wires, and dialysis catheters
Justin M. Robbins, Anil Hingorani, and Enrico Ascher
28 Indications, techniques, and results of inferior vena cava lters
Courtney E. Morgan and John E. Rectenwald
29 Supercial thrombophlebitis
Suman Wasan
30 Mesenteric vein thrombosis
Elizabeth A. Andraska and Mohammadreza Zaris
https://t.me/med1917
CHAPTER
17
https://t.me/med1917
The clinical presentation and natural
history of acute deep venous thrombosis
Jake F. Hemingway and Mark H. Meissner
17.1 INTRODUCTION
The spectrum of venous thromboembolism (VTE) includes
both deep venous thrombosis (DVT) and pulmonary
embolism (PE). Estimates suggest an incidence of 857,000,
370,00, and 1,220,000 for DVT, PE, and VTE, respectively,
in the United States in 2016.
over the past 2 decades, although much of this increase
may be associated with more accurate and increased use
of diagnostic studies.
prospective, multicenter registry, 72.7% had DVT, 9.7%
had PE, and 17.5% had both DVT and PE.
sodes of clinically recognized DVT occur with an age-adjusted incidence of 50.4 per 100,000 person-years, and
the lifetime risk of VTE at age 45 has been estimated to
be 8.1%.
and the symptoms of acute DVT, including edema, pain,
and erythema, are nonspecic.
within the venous system depends in large measure on
imbalances within the coagulation and brinolytic systems,
and similar interactions continue to be important throughout the subsequent evolution of these thrombi. Over time,
the processes of recanalization and organization compete
with thrombus extension and rethrombosis. Recurrent
thrombosis and post-thrombotic syndrome dominate the
late natural history of acute DVT. The treatment of DVT
is aimed at preventing its complications—recurrent DVT,
post-thrombotic syndrome, and death. These complications are closely related to the natural history of DVT, an
understanding of which is required in determining optimal
management.
1,4
However, many episodes are asymptomatic,
1
Rates of VTE have increased
2
Among 2119 patients enrolled in a
3
First epi-
3
The formation of thrombi
17.2 CLINICAL PRESENTATION OF
ACUTE DVT
The clinical presentation of an acute DVT varies with the
anatomic distribution, extent, and degree of occlusion of
the thrombus. Symptoms accordingly range from being
absent to massive swelling and cyanosis with impending
venous gangrene (phlegmasia cerulea dolens). Although
DVT has historically been characterized as involving the
proximal or distal veins, there are in fact three anatomic
patterns—isolated calf vein (distal), femoropopliteal, and
iliofemoral thrombosis, which have somewhat different
natural histories. The guidelines of the Society for Vascular Surgery and the American Venous Forum (SVS/AVF)
accordingly recommend the use of precise anatomic terminology to characterize the most proximal extent of venous
thrombosis as involving the iliofemoral veins, with or without extension to the inferior vena cava, the femoropopliteal veins, or isolated to the distal calf veins.
Symptoms tend to be more severe as thrombosis extends
proximally. When present, signs and symptoms of acute
DVT may include pain, edema, erythema, tenderness, fever,
prominent supercial veins, pain with passive dorsiexion
of the foot (Homan sign), and peripheral cyanosis. Isolated
calf vein thrombosis, which comprises approximately 50%
of all DVTs, tends to be associated with worse pain but
decreased swelling in comparison to proximal DVT.
bly, up to 50% of patients with an acute DVT may lack
specic signs and symptoms, and postoperative patients
are, in particular, more likely to have small, asymptomatic,
distal, nonocclusive thrombi.
ciated with concurrent DVT, a palpable cord is more suggestive of supercial venous thrombosis.
Phlegmasia cerulea dolens, characterized by the triad
of massive swelling, cyanosis, and pain, is the most severe
form of acute DVT and results from near-complete thrombosis of an extremity’s venous outow.
it is marked by severe venous hypertension with collateral
and microvascular thrombosis leading to venous gangrene.
Venous gangrene has been particularly associated with
warfarin-mediated protein C depletion in patients with
cancer and heparin-induced thrombocytopenia.
The diagnosis of acute DVT based upon clinical signs
and symptoms alone is notoriously inaccurate. The signs
and symptoms are nonspecic and may be associated with
other lower extremity disorders including lymphedema,
post-thrombotic syndrome, supercial venous thrombosis,
cellulitis, musculoskeletal trauma, and Baker cysts. Among
patients referred to the vascular laboratory for exclusion
of DVT, only 12%–31% will have a positive ultrasound
12–14
study.
extremity ndings, 3.3% of which will be signicant.
range of reported sensitivities and specicities, including
calf pain (sensitivity 75%–91%, specicity 3%–87%) and
calf swelling (sensitivity 35%–97%, specicity 8%–88%),
However, 12.8% will have incidental lower
The most common presenting symptoms have a wide
7,8
Although potentially asso-
5
6
Nota-
9
In advanced cases,
10,11
15
DOI: 10.1201/9781003328971-20
177177
178 Chapter 17 The clinical presentation and natural history of acute deep venous thrombosis
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and none of the signs or symptoms are sufciently sensitive
or specic, either alone or in combination, to accurately
diagnose or exclude thrombosis based on exam and clinical presentation alone.
16–22
For example, although Markel
found a history of swelling in 83% of patients with a DVT,
it was also present in 63% of those with a clinical suspicion
but no documented DVT.
13
Limb pain was similarly present in 51% and 41% of patients with and without DVT,
respectively. The overall sensitivity and specicity of the
clinical examination have ranged from 60% to 96% and
20% to 72%, respectively.
23
The accuracy of the clinical evaluation also differs
between inpatients and outpatients. Inpatients are more
likely to have undergone surgery or to be critically ill,
while outpatients are less likely to have had recent surgery,
trauma, or a prior DVT.
12
Additionally, the incidence of
DVT is lower among outpatients, while specic leg symptoms are more common. The absence of certain risk factors, signs, or symptoms may thus have a higher negative
predictive value in outpatients.
14
As the clinical presentation of acute DVT is nonspecic,
the presence or absence of associated thrombotic risk factors may alter diagnostic suspicion. For example, in outpatients without cancer, a duration of symptoms greater than
7 days and a differential thigh circumference of <3cm has
a negative predictive value of 95%.
14
Unfortunately, the
positive predictive value is only 28.6%. Similarly, a difference in calf circumference of <2cm demonstrated a negative predictive value of 85% among outpatients and 93%
among inpatients.
12
However, when combined with the
absence of risk factors, the negative predictive value of the
absence of swelling increased to 97% in outpatients and
92% in inpatients. Despite these observations, withholding
treatment based only on empiric clinical observations poses
an unacceptable thromboembolic risk of up to 2%–4% in
secondary referral outpatients, 8% in inpatients, and 12%
in primary care patients.
12,14,24
Further diagnostic testing
is therefore usually necessary, both to ensure appropriate
treatment of those with conrmed DVT and to prevent the
complications of inappropriate anticoagulation in those
with other disorders.
Clinical assessment does have a role in determining pretest probability in algorithms incorporating further diagnostic modalities such as venous duplex ultrasonography
and D-dimer measurements.
oped and validated by Wells has been used most widely.
25
The probability model devel-
26
The model effectively straties patients into low, moderate,
and high pretest probability groups based on the presence
of cancer, lower extremity immobilization by paralysis or
plaster dressings, recent surgery or bed rest longer than 3
days, thigh and calf swelling, tenderness along the course of
the deep veins, a >3cm increase in calf circumference, pitting edema, collateral supercial veins, and the possibility
of an alternative diagnosis. Avalid alternative diagnosis,
most often cellulitis or musculoskeletal disorders, is present
in 56% of those without DVT in comparison to only 17%
of those with a conrmed DVT.
27,28
Unfortunately, although
such models are useful in guiding further diagnostic tests,
the 3% prevalence of DVT in low-probability patients precludes diagnosis based on clinical strategies alone.
26
Fortunately, D-dimer has an excellent negative predictive value
in low-probability outpatients, and algorithms combining
clinical pretest probability assessment, D-dimer measurement, and venous duplex ultrasound have been developed
and validated.
25
Delayed diagnosis of DVT is not uncommon. Among
2047 patients with symptomatic DVT, a diagnosis was
established within 5 days of the onset of symptoms in only
47.1%, while it was delayed beyond 10 days in 22.6%.
Much of this time can be attributed to delays in presentation, as patients, on average, present 4.4 days after the
onset of symptoms.
shorter, many of these can be attributed to inadequate
appreciation of a patient’s underlying risk factors.
29
Although diagnostic delays are often
3,29
17.3 COMPLICATIONS OF ACUTE DVT
17.3.1 Pulmonary embolism
The potentially life-threatening consequences of PE make
it the most important short-term complication of acute
DVT. Symptomatic PE accompanies approximately 10%
of DVTs.
between 29 and 78 per 100,000.
substantially increased since 2001, likely related to the
increased availability of CT and MRpulmonary angiography.
tality rate in France declined by 3% per year between 2000
and 2010.
the presence or absence of objectively documented PE, and
as many as 75% of PE may be asymptomatic.
diagnostic testing suggests that PE accompanies acute DVT
much more frequently than appreciated clinically. As many
as 25%–52% of patients with documented DVT but no
symptoms of PE will have high-probability lung scans at
presentation.
of symptomatic PE, high-probability scans have also been
noted in 18%–29% of patients with isolated calf vein
thrombosis, and in hospitalized patients, isolated calf vein
DVT has been associated with a high prevalence of concurrent PE (33%).
vein thrombosis is more likely to be associated with PE
and recurrent thromboembolism than muscular vein
thrombosis.
and presenting features. The American Heart Association
recommends stratifying patients into massive, submassive,
and nonmassive categories.
by sustained hypotension (systolic blood pressure <90
mmHg), pulselessness, or persistent profound bradycardia; submassive PE by evidence of right ventricular dysfunction (echocardiography, computed tomography, BNP,
or pro-BNP) or myocardial necrosis (troponin Ior T); and
nonmassive PE by normotension with normal RV function
and biomarkers. Mortality varies from 25% to 52.4%
for massive PE to approximately 1% for nonmassive PE.
Other predictive models, most notably the simplied Pulmonary Embolism Severity Index (sPESI), have also been
developed to predict 30-day mortality after PE.
ables (age >80, history of cancer, chronic lung disease or
congestive heart failure, pulse >110, systolic blood pressure
<100 mmHg, and oxygen saturation <90%) are used to
30
The incidence of isolated PE is estimated to be
31
Despite this observation, the age-adjusted PE mor-
32
31
The incidence of PE has
However, respiratory symptoms correlate poorly with
33,34
Routine
33–36
Although regarded as an unusual source
37
Among isolated calf vein DVT, axial
38
The outcomes after PE vary with patient comorbidities
39
Massive PE is characterized
40
Six vari-
3
17.4 The natural history of acute DVT 179
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stratify patients into low- and high-risk groups with a corresponding 30-day mortality of 2.5% and 10.9%, respectively.
17.3.2 Post-thrombotic syndrome
Post-thrombotic syndrome, with symptoms including pain,
edema, skin changes, and ulceration, is the most important late complication of DVT. Older studies, many with
methodological aws, reported post-thrombotic manifestations in up to two-thirds of patients with an acute DVT.
More recent studies suggest that although the incidence
of post-thrombotic syndrome is still underappreciated, it
occurs less commonly than in historical studies. Among
224 patients followed for 5 years after venographically
conrmed DVT, post-thrombotic syndrome developed in
29.6% of those with proximal thrombosis and 30% of
those with isolated calf vein thrombosis.
41
Recurrent ipsilateral DVT in particular is associated with developing
post-thrombotic syndrome, as recurrent ipsilateral DVT is
associated with a sixfold increased risk. Additional predictors of developing post-thrombotic syndrome, as identied
in various studies, include elevated body mass index (BMI
≥26), Villalta score ≥2, duration of symptoms at the time
of diagnosis for ≥8 days, iliofemoral involvement, active
cancer, history of prior VTE, chronic venous insufciency,
and compression stocking use for less than 6 months.
42,43
Population-based studies evaluating the prevalence
of post-thrombotic syndrome have suggested that, in
the United States, 6–7million people have skin changes,
while ulceration is present in 400,000–500,000 people.
44
In addition to the substantial economic costs, the physical
limitations of patients with post-thrombotic syndrome are
comparable to those of patients with other serious chronic
medical conditions.
30
17.3.3 Mortality after acute DVT
Mortality after an episode of acute DVT exceeds that
expected in age-matched populations. Although the in-hospital case-fatality rate for DVT is only 5%; 1-, 3-, and
5-year mortality rates of 22%, 30%, and 39%, respectively,
have been noted.
and use of imaging technology, 30-day (5.1%) and 1-year
(21.5%) mortality among Medicare beneciaries in the
United States have not changed substantially over the past
decade.
1
Early mortality is most frequently secondary to
cancer, PE, or cardiac disease. It is notable that even asymptomatic DVTs identied by ultrasound are associated with
a threefold increase in short-term all-cause mortality in
medically ill patients.
cancer is the most important predictor of early death, with
28-day mortality rates among those with cancer being as
high as 25.4%.
ity rate in patients without cancer, 1-year mortality rates
are as high as 63.4%.
patients and those with idiopathic DVT remain high for
at least 3years beyond the index event, mortality rates for
those with secondary VTE unrelated to cancer return to
those of the general population after 6 months.
Atherosclerosis and VTE share many risk factors
including age, sex, obesity, smoking, and inammation.
DVT is accordingly associated with an increased risk of
30,45,46
Despite the widespread availability
1
Among patients ≥45years of age,
47,48
In comparison to the 12.6% mortal-
45
Although deaths among cancer
45
49
cardiovascular morbidity and mortality.
50
The 10-year cumulative risk of a symptomatic vascular event among patients
with idiopathic DVT is 25.4% in comparison to 12.9% in
those with secondary VTE.
51
Patients with idiopathic DVT
also have a higher prevalence of atherosclerotic risk factors
(diabetes, hypertension, and hypercholesterolemia) and
coronary artery calcium than controls without VTE.
presence of residual thrombus at the time anticoagulants
are stopped may be a marker for subsequent cardiovascular events.
50,53
Patients with residual venous obstruction 3
months after a symptomatic DVT are 2.5-fold more likely to
develop recurrent VTE, post-thrombotic syndrome, cancer,
or have an arterial thrombotic event.
54
Although the reasons for this are not clear, it has been postulated that the
presence of residual thrombus is associated with generalized
hypercoagulability. Such a relationship is supported by the
higher levels of activated coagulation seen in DVT patients
with cardiac disease and the observation that both delayed
recanalization and myocardial infarction are associated with
increased levels of plasminogen activator inhibitor (PAI-
55,56
Several trials have now demonstrated up to a 47%
1).
reduction in the risk of VTE with the use of statins.
17.4 THE NATURAL HISTORY OF
ACUTE DVT
17.4.1 Venous thrombogenesis
As initially proposed by Virchow, three factors are
of primary importance in the development of venous
thrombosis—abnormalities of blood ow, abnormalities of
blood, and vessel wall injury. However, despite the accuracy of Virchow’s postulates, it is now apparent that all
three components are not equally important in individual
patients. The role of structural injury to the venous wall is
disputable—even in the presence of stasis, overt endothelial
injury appears to be neither a necessary nor sufcient condition for thrombosis.
venous trauma, hip arthroplasty, and central venous catheters, there is little evidence that gross venous injury plays
a signicant role in most thromboses. In contrast, data are
accumulating that biologic injury to the endothelium may
have a very important role in venous thrombogenesis. The
venous endothelium is normally antithrombotic, producing
prostaglandin I
gen activator (t-PA), and glycosaminoglycan cofactors of
antithrombin. Under conditions favoring thrombosis, the
endothelium may become prothrombotic, producing tissue factor, von Willebrand factor, and bronectin. Leukocytes may be a key mediator of both endothelial injury and
hypercoagulability, with the early phases of thrombosis
marked by increases in permeability followed by leukocyte
adhesion, migration, and endothelial disruption.
ciated cytokines may also be of importance, with factors
such as interleukin 1 (IL-1) increasing tissue factor expression while diminishing protein C activation.
Although most venous thrombi originate in areas of
low blood ow, stasis alone is also an inadequate stimulus in the absence of low levels of activated coagulation
factors.
62,63
Although stasis may facilitate endothelial
58
With the notable exceptions of direct
, thrombomodulin, tissue-type plasmino-
2
59,60
61
52
57
Asso-
17
The
180 Chapter 17 The clinical presentation and natural history of acute deep venous thrombosis
https://t.me/med1917
leukocyte adhesion and cause endothelial hypoxia leading to
a procoagulant state, its most important role may be in permitting the accumulation of activated coagulation factors in
areas prone to thrombosis.
59,64
Stasis may thus be a permis-
sive factor for the other events required for thrombosis.
Imbalanced activation of the coagulation system appears
to be the most important factor underlying many episodes of
acute DVT. Although the hemostatic system is continuously
active, thrombus formation is ordinarily conned to sites of
local injury by a precise balance between activators and inhibitors of coagulation and brinolysis. A prethrombotic state
may result either from imbalances in the regulatory and inhibitory systems or from activation exceeding antithrombotic
capacity.
65
Some components of imbalanced coagulation
appear to be associated with most thrombotic risk factors
including age, malignancy, surgery, trauma, primary hypercoagulable states, pregnancy, and oral contraceptive use.
Based on perceived differences in the natural history,
lower extremity venous thrombi are classied as involving the iliofemoral, femoropopliteal, or calf veins.
5
These
thrombi originate in areas where imbalanced coagulation
is localized by stasis in the soleal sinuses, behind venous
valve pockets, at venous conuences, and distal to areas of
extrinsic compression. This is a very important and often
misunderstood concept—VTE is fundamentally a disease
of coagulation, localized to regions of stasis, rather than a
disease of the veins themselves. The calf veins are the most
common site of origin, although 40% of proximal thrombi
arise primarily in the femoral or iliac veins. In the femoral
veins, these presumably occur in regions behind the valves,
while in the iliac veins, DVT is frequently associated with
compression of the left common iliac vein by the overlying right common iliac artery (May–Thurner syndrome).
66
In ow models, vortices produced beyond the valve cusps
tend to trap red cells in a low shear eld near the apex
of the cusp.
in vivo using B-ow ultrasound.
forming within these eddies are likely the early niduses
for thrombus formation.
67
Such vortices have also been demonstrated
69
However, such aggregates are
68
Red cell aggregates
probably transient until stabilized by brin in the setting of
locally activated coagulation. After their formation, these
early thrombi may become anchored to the endothelium
near the apex of the valve cusp, a process postulated to be
mediated by adherent leukocytes.
60,70,71
Propagation of thrombi beyond areas of stasis probably
depends largely on the relative balance between activated
coagulation and thrombolysis. If local conditions favor
propagation, laminated appositional growth occurs outward from the apex as platelets are surrounded by a red cell,
brin, and leukocyte network. In contrast to arterial thrombi,
venous thrombi are composed largely of red cells and brin
with relatively few platelets. Once luminal ow is disturbed,
prograde and retrograde propagation may also be promoted
by hemodynamic factors. Conversely, such early thrombi
may fail to propagate, with aborted thrombi appearing as
endothelialized brin fragments within the valve pockets.
17.4.2 Recanalization
Once formed, the competing processes of recanalization
and recurrent venous thrombosis characterize the natural history of acute DVT. The development of chronic
sequelae is closely related to the balance between these
two processes. The venous lumen is most often re-established after both experimental and clinical thrombosis.
The mechanisms of thrombus organization and recanalization have been extensively investigated in animal models
of DVT. Both the vein wall and thrombus play important
roles in these processes. In short, there is rapid regeneration of a brinolytically active neoendothelium soon after
thrombosis, with an early neutrophilic inltrate within
the thrombus and vein wall followed by a predominantly
monocyte inltrate.
71,72
Monocytes appear to play a particularly important role in thrombus organization and recanalization, functioning as a source of both brinolytic and
cytokine mediators. Experimental thrombi show complete
recanalization by 3 weeks, with the thrombus reduced to
an endothelialized subintimal streak.
Although less extensively investigated, histologic studies
suggest that clinical DVT follows a similar course. As in the
animal models, recanalization appears to be a complex process involving intrinsic (arising within the thrombus) and
extrinsic brinolysis, peripheral fragmentation, neovascularization, and retraction. Thrombus organization begins in
the attachment zone with the migration of surfacing cells,
presumably derived from the endothelium, over the throm-
73
Pockets formed between the thrombus and the vein
bus.
walls then progressively enlarge through peripheral fragmentation and brinolysis. The thrombus simultaneously
undergoes central softening as well as contraction. In the
absence of propagation, the ultimate result is a restored
venous lumen with a slightly raised broelastic plaque at
the site of initial thrombus adherence to the vein wall.
Serial noninvasive diagnostic tests, permitting venous
thrombi to be followed over time, have conrmed the
clinical importance of these processes. Among 21 patients
prospectively followed with ultrasound, Killewich noted
that some recanalization was present by 7 days in 44%
of patients and by 90 days in 100% of patients.
percentage of initially involved segments that remained
occluded decreased to a mean of 44% by 30 days and 14%
by 90 days. Van Ramshorst etal. similarly noted an exponential decrease in thrombus load over the rst 6 months
after femoropopliteal thrombosis.
75
Most recanalization
occurred within the rst 6 weeks, with ow re-established
in 87% of 23 completely occluded segments during this
interval. Approximately 55% of subjects will show complete recanalization within 6–9 months of thrombosis.
However, some reduction in thrombus load may continue,
albeit at a slower rate, for months to years after the acute
event (Figure17.1). Notably, clinical studies assessing twopoint compressibility in the common femoral and popliteal
veins have demonstrated similar rates of incomplete recanalization (49.4%) at 3 months.
54
Although thrombus resolution proceeds at a similar rate
in the femoropopliteal venous segments, some have found
more rapid clearance from the tibial segments, perhaps
reecting the increased efciency of thrombolysis in small
56,78
veins.
In contrast, recanalization of thrombosed iliac
segments is slower and more often incomplete. Iliofemoral
venous patency rates may be as low as 24%, 18%, and
18% at 1, 3, and 5years after DVT, respectively.
79
The degree of recanalization is related to both the
degree of activated coagulation and brinolytic inhibi-
74
The
76,77
70
17.4 The natural history of acute DVT 181
Follow-up interval
Thrombus score
12
Prothrombin fragment 1+2 (nmol/L)
Percent recanalization
(a) (b)
Percent recanalization
0
https://t.me/med1917
10
8
6
4
2
0
Day 0 Day 3 Day 7 Day 14 1 month3 months6 months9 months1 year
17.1 Boxplot shows reduction in thrombus score determined by serial ultrasound examinations over the rst year after DVT. Top,
middle, and bottom lines of the box represent the 75th, 50th (median), and 25th percentiles, respectively. Closed square shows the
mean, with top and bottom error bars representing the 90th and 10th percentiles, respectively. Progressive recanalization occurs
with a reduction in mean thrombus score from 5.1 at the time of presentation to 1.8 at 12 months. Mean percent recanalization was
52.4% at 6 months, 57.9% at 9 months, and 58.8% at 12 months.
Source: (Meissner MH, Zierler BK, Bergelin, RO etal. Coagulation, fibrinolysis, and recanalization after acute deep venous thrombosis. J Vasc Surg 2002;
35: 278–285. Reprinted with permission.)
17
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
–60 –50 –40 –30 –20 –10 0 10 20
30 40 50 60 70 80 90 100
17.2 Scatterplot of percent recanalization versus prothrombin fragment 1 + 2 (a) and plasminogen activator inhibitor (PAI-1) activity
(b) at presentation among patients followed at least 9 months (n=44). Solid regression lines show correlation between recanalization
and initial F 1+ 2 (R=–0.53, P=0.0004) and PAI-1 (R=–0.48, P=0.002) levels. Patients with negative percent recanalization values
had progression of thrombus during follow-up.
Source: (Meissner MH, Zierler BK, Bergelin, RO etal. Coagulation, fibrinolysis, and recanalization after acute deep venous thrombosis. J Vasc Surg 2002;
35: 278–285. Reprinted with permission.)
tion (Figure17.2). Recanalization is negatively correlated
with levels of thrombin activation products (prothrombin
fragment 1 + 2) at the time of presentation.
found higher PAI-1 levels in patients with poor thrombus resolution.
56,77
From a clinical perspective, more com-
56
Others have
plete recanalization has been reported in older patients,
25
20
15
PAI-1 (U/mL)
10
5
0
–60 –50 –40 –30 –20 –10 0 10 20
those with asymptomatic postoperative thrombosis, and
patients with involvement of only one venous segment.
30 40 50 60 70 80 90 10
80
Cancer is associated with less complete recanalization.
The presence of a permanent risk factor has also been
associated with an 11-fold higher risk of delayed recanalization.
81
182 Chapter 17 The clinical presentation and natural history of acute deep venous thrombosis
N 71 49 32 17
21
40
Cumulative incidence of recurrent DVT (%)
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17.4.3 Recurrent venous thrombosis
Recurrent thrombotic events compete with recanalization early after an acute DVT. Most clinical studies have
included both symptomatic recurrent DVT and PE, with
rates depending on treatment, proximal or distal location
of thrombus, and duration of follow-up. Fortunately, standard anticoagulation is very effective in preventing recurrent
VTE while on treatment. Among patients with proximal
DVT, recurrent thromboembolic events occurred in 5.2%
of patients treated with standard anticoagulation measures
for 3 months in comparison to 47% of patients inadequately
treated with a 3-month course of low-dose subcutaneous
heparin.
VTE during 3 months of anticoagulant treatment.
recent randomized comparisons of the direct thrombin
(dabigatran etexilate) and factor Xa (rivaroxaban, apixaban, and edoxaban) inhibitors to warfarin have demonstrated similar rates of recurrent VTE for the direct oral
anticoagulants (2.1%–3.2%) and warfarin (1.8%–3.5%)
over the initial 3–12 months of treatment.
agulation, either acute or chronic, it is not surprising that
most symptomatic events occur after anticoagulation has
been stopped. The risk of recurrence is at least as great in
the contralateral as in the ipsilateral extremity.
and Bounameaux calculated a theoretical recurrence rate
of 0.9% per month after discontinuing anticoagulant therapy for proximal DVT, similar to observed annual recurrence rates of 7.0%–12.9%.
VTE is highest over the rst 6–12 months after the index
event, although cumulative rates are as high as 24% at
5years and 30% at 8years after initial presentation.
Among 1626 patients followed after a rst episode of VTE,
the cumulative incidence of recurrence after discontinuing
anticoagulation was 11.0%, 19.6%, 29.1%, and 39.9% at
1, 3, 5, and 10years, respectively.
ing thrombotic risk factors. In comparison to those with
provoked DVT, the risk of recurrence is two- to threefold
higher among those with idiopathic thrombosis.
However, even though the 10-year risk of recurrence may
be as high as 52.6% in patients with idiopathic VTE, it
is not inconsequential (22.5%) in patients with secondary
provoked thrombosis.
atic recurrent DVT include advanced age, male gender,
increased BMI, lower extremity paresis, active malignancy,
and a shorter duration of anticoagulation.
the inherited thrombophilias as a risk factor for recurrent VTE remains controversial. While some congenital
thrombophilias, including antithrombin and protein C and
S deciency, hyperhomocysteinemia, and increased levels of factors VIII and XI, appear to be associated with
an increased risk of recurrence, the data supporting an
increased risk associated with the common factor V Leiden
and prothrombin G20210A mutations are conicting.
Several clinical models for predicting the risk of recurrent
thrombosis have been developed but await prospective validation.
related to thrombus location. Proximal venous thrombosis
is associated with a 3-fold higher risk of recurrence than
isolated calf vein thrombosis, and iliofemoral thrombosis is
82,83
Others have reported a 7% rate of recurrent
85
84
More
As VTE is fundamentally a disease of disordered antico-
86
Sarasin
47,53,87
The risk of recurrent
53,84,86
88
The risk of recurrence is highly related to the underly-
53,84,88
88
Specic risk factors for symptom-
88,89
The role of
90
Finally, the risk of recurrence also appears to be
90
associated with a 2.4-fold higher risk than femoropopliteal
thrombosis.
91
Recurrent DVT after isolated calf vein thrombosis
requires special consideration. Limited data suggest that isolated calf vein thrombosis is associated with less extensive
activation of coagulation than proximal venous thrombosis, perhaps implying some difference in pathophysiology.
At least two types of calf vein thrombosis may be differentiated—those with involvement of the paired posterior
tibial and peroneal venae commitantes (axial calf vein
thrombosis) and those isolated to the veins draining the gastrocnemial and soleal muscles (muscular calf vein thrombosis)—and their natural history may be different. In patients
with thrombosis isolated to the axial calf veins, proximal
propagation occurred in 23% of untreated patients and
10% of patients treated with only intravenous heparin.
As ultrasound technology has improved, muscular calf
vein thrombi are more often identied and now account
for approximately 40% of isolated calf vein thrombi. The
natural history of these thrombi has only recently been
described. Among 135 limbs followed after isolated muscular calf vein thrombosis, 16.3% propagated to the axial
tibial veins or higher, the majority (90.9%) within 2 weeks
of presentation, and only 2.9% to the level of the popliteal vein.
93
Cancer was the only risk factor associated with
propagation of these thrombi. Although such data suggest
that thrombosis isolated to the muscular calf veins may be
more benign than that involving the axial calf veins, there
are conicting reports of associated PE in 7% of patients at
the time of presentation and long-term recurrence rates of
18.8%.
history and management of these thrombi.
94
More information is needed regarding the natural
Not surprisingly, noninvasive natural history studies
have disclosed a much higher rate of asymptomatic recurrence than is suggested by clinical studies. Serial duplex
studies have shown propagation of thrombus in 26%–38%
of treated patients within the rst few weeks after presentation (Figure17.3).
95,96
In a larger series of 177 patients followed for a median of 9.3 months, ultrasound-documented
recurrent thrombotic events were observed in 52% of
30
20
10
0
0
17.3 Cumulative incidence of ultrasound-documented recur-
rent thrombotic events during the rst 3 weeks of therapy.
Source: (Caps MT, Meissner MH, Tullis MJ, Polissar NL, Manzo RA, Zierler
BK, Chandler WL, Strandness DE. Venous thrombus stability during acute
phase of therapy. Vasc Med. 1999; 4: 9–14. Reprinted with permission.)
7 14
Time (days)
25.9%
55
92
17.5 The natural history of DVT and post-thrombotic syndrome 183
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patients.97 Among initially involved extremities, propagation to new segments occurred in 30% and rethrombosis of
a partially occluded or recanalized segment in 31%. New
thrombi were also observed in 6% of initially uninvolved
contralateral extremities.
Although asymptomatic ultrasound-documented recurrences are not clearly associated with underlying risk
factors, they are related to the degree of activated coagulation and the adequacy of anticoagulation.
97
Initial levels
of thrombin activation products (prothrombin fragment
1 + 2) and D-dimer are signicantly higher in patients with
subsequent ultrasound-documented recurrence.
55
Elevated
D-dimer levels after discontinuing anticoagulation have
also been associated with a higher risk of symptomatic
clinical recurrence.
98
In the case of isolated calf vein thrombosis, D-dimer levels ≥2000 ng/mL at the time of presentation had a sensitivity and specicity of 88.9% and 76.5%,
respectively, in predicting recurrent events. Asymptomatic
recurrence is prevented by adequate anticoagulation, and
thus the risk of new thrombotic events increases 1.4-fold
for each 20% reduction in the time that anticoagulation
is adequate, according to standard laboratory measures.
96
Recanalization and recurrent thrombosis may in fact
be related. Among 313 patients followed for up to 6years
after a rst episode of DVT, 41 of 58 episodes of recurrent VTE occurred in patients with residual thrombus pres-
84
However, the importance of residual thrombus as a
ent.
predictor of recurrent DVT remains controversial. While
some have found a 2.2- to greater than 5-fold increased
risk of recurrent thrombosis among those with incomplete
recanalization,
relationship.
53,80
others have failed to demonstrate such a
99,100
Ameta-analysis including 3531 patients
from 13 studies suggested that residual venous obstruction after discontinuing anticoagulation was not associated
with recurrent VTE in patients with idiopathic DVT (odds
ratio 1.35, 0.87–2.08), although a signicant relationship
was present in secondary VTE (2.78, 1.41–5.50) that was
attributable to an increased risk in patients with cancer.
101
As many recurrent events occur in the contralateral leg or
are episodes of PE, it is likely any risk of residual thrombus is related to underlying hypercoagulability rather than
mechanical abnormalities of the venous system.
presence of ongoing hypercoagulability is, in fact, perhaps a
better predictor of the risk of recurrent VTE.
50,53
102
At least one
The
study has found that although residual thrombus was not
an independent predictor, a D-dimer level of >500 ng/mL
measured 1 month after discontinuing anticoagulants was
associated with a 3.3-fold increased risk of recurrence.
99
17.5 THE NATURAL HISTORY OF
DVT AND POST-THROMBOTIC
SYNDROME
17.5.1 Pathophysiology of
post-thrombotic syndrome
As discussed earlier, manifestations of post-thrombotic
syndrome include pain, edema, skin changes, and ultimately ulceration. At least three scoring systems—the
Ginsberg criteria,
103
the Villalta scale,
Clinical Severity Score
105
—have been developed for clas-
104
and the Venous
sifying the clinical severity of post-thrombotic syndrome,
and the incidence varies widely with the system used.
Although there are some concerns that the Villalta scale
may be overly sensitive to mild post-thrombotic disease, it
has been the most widely used in clinical studies. Among
355 patients evaluated with the Villalta instrument after a
rst episode of DVT, the cumulative incidence of any and
severe post-thrombotic syndrome at 5years was 28% and
9.3%, respectively.
41
Ambulatory venous hypertension, resulting from a
combination of venous reux and obstruction, is responsible for the more severe post-thrombotic sequelae. Although
experimentally produced thrombi frequently recanalize to
produce a patent but valveless lumen, valvular destruction is not a universal consequence of clinical DVT. Many
patients remain free of chronic symptoms after an episode
of acute DVT, and only 69% of extremities have ultrasound-documented reux 1year after thrombosis.
incidence of reux in individual venous segments is even
lower, with only 33%–59% of involved segments becoming incompetent.
Histologic examination of post-thrombotic veins
provides some explanation for the differential development of reux after DVT. In extremities with established
post-thrombotic syndrome, approximately 50% of popliteal valves will demonstrate thrombus formation on the
valve leaets, while others show endothelial erosion with
basement membrane thickening and atypical subintimal
collagen bers.
107
However, most episodes of acute DVT
are not associated with such extensive histologic changes.
In contrast to the observations in patients with established
post-thrombotic syndrome, early brocellular organization
after an acute DVT rarely involves the valve cusps.
Thrombus adherence to the valve cusp was noted in only
4 of 44 specimens examined by Sevitt.
cases, the thrombus was separated from the valve cusp by
108
In the majority of
a cleft postulated to arise from the local brinolytic activity of the valvular endothelium. These observations likely
reect the intense plasminogen activator activity of the
venous valve cusps, which may act to preserve some valves
during recanalization.
These histologic observations are consistent with the
natural history of valvular reux. Serial duplex studies
have shown the development of reux to coincide with or
slightly precede complete recanalization of a segment.
with recanalization, the rate at which reux develops is
highest during the rst 6–12 months after DVT.
may be transient in up to 23% of involved segments,
resolving during the course of follow-up.
109
109
This phenomenon conceivably occurs when valves protected by the lytic
clefts described earlier remain partially encumbered by
residual thrombus. Normal valvular function then presumably returns with complete recanalization.
Despite the importance of venous reux, limbs developing edema, skin changes, or ulceration are more likely to
have a combination of reux and residual obstruction than
either abnormality alone (Figure17.4).
21
In addition to its
direct effects on ambulatory venous pressure, obstruction
may indirectly contribute to the development of reux.
As many as 30% of segments developing reux during
106
The
73,108
78
As
Reux
17
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