- Email: [email protected]
Chronic pulmonary embolism in Klippel-Trenaunay syndrome
Chronic pulmonary embolism in Klippel-Trenaunay syndrome Renee A. Douma, MD, PhD,a* Charlene E. U. Oduber, MD, PhD,b* Victor E. A. Gerdes, MD, PhD,a,i Otto M. van Delden, MD, PhD,c Berthe L. F. van Eck-Smit, MD, PhD,d Joost C. M. Meijers, PhD,e Eduard J. van Beers, MD, PhD,f Berto J. Bouma, MD, PhD,g Chantal M. A. M. van der Horst, MD, PhD,b and Paul Bresser, MD, PhDh,j Amsterdam, The Netherlands Background: Klippel-Trenaunay syndrome (KTS) is characterized by vascular malformations and disturbed soft tissue or bony growth, involving one or more extremities. A high incidence of venous thromboembolism (VTE) has been reported in this disorder, along with cases of belated diagnosed chronic thromboembolic (CTE) pulmonary hypertension (CTEPH). We performed a cross-sectional study to investigate the prevalence of CTE in patients with KTS. Methods: Those from our KTS patient cohort willing to participate were examined with a sequential diagnostic workup including perfusion scintigraphy, computed tomography, and echocardiography. Results: Of 68 patients, 48 patients participated in the study (median age 43 years; 29 [60%] were female). Eleven patients (23%) had an abnormal perfusion scan result, of whom computed tomographic scanning showed signs of CTE in two patients (4.2%; 95% confidence interval [CI] 1.2%-14%); both patients had a history of VTE. Echocardiography showed no signs of CTEPH in these patients. In total, 23 patients (48%; 95% CI 35%-62%) had a history of superficial vein thrombosis and 8 patients (17%; 95% CI 8.7%-30%) had a history of deep vein thrombosis or pulmonary embolism, which was associated with more shortness of breath. Limitations: Echocardiography was only performed in patients with CTE. Conclusion: A large proportion of patients with KTS had a history of VTE. The prevalence of CTE in the total KTS cohort, however, appeared less alarming than previously assumed. Based on these results, we suggest that there is only a limited indication for CTEPH screening among patients with KTS. Nevertheless, awareness for CTEPH remains appropriate, especially among patients presenting with shortness of breath and a history of VTE. ( J Am Acad Dermatol 2012;66:71-7.) Key words: chronic thromboembolic pulmonary hypertension; chronic thromboembolism; KlippelTrenaunay syndrome; pulmonary embolism; vascular malformations; venous thromboembolism.
From the Departments of Vascular Medicine,a Plastic, Reconstructive, and Hand Surgery,b Radiology,c Nuclear Medicine,d Experimental Vascular Medicine,e Internal Medicine and Hematology,f Cardiology,g and Respiratory Medicine,h Academic Medical Center; Department of Internal Medicine, Slotervaart Hospitali; and Department of Respiratory Medicine, Onze Lieve Vrouwe Gasthuis.j *These authors contributed equally. Funding sources: None. Conflicts of interest: None declared. Accepted for publication December 4, 2010. Reprint requests: Renee A. Douma, MD, Department of Vascular Medicine, Academic Medical Center, Suite F4-143, Meibergdreef 9, PO Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: [email protected]. Published online May 16, 2011. 0190-9622/$36.00 Ó 2011 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.12.002
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lippel-Trenaunay syndrome (KTS) is characterized by a combination of capillary, venous, and lymphatic malformations, and a localized disturbed growth of bone and/or soft tissues (Fig 1).1-5 The syndrome occurs in all ethnic groups, with an estimated prevalence of 1/20,000 to 1/100,000 live births.6-8 Clinical presentation may vary from being asymptomatic to developing potentially life-threatening complications, such as deep vein thrombosis (DVT), pulmonary embolism (PE), and recurrent bleeding.4,9-11 Venous thromboembolism (VTE) has been reported in 8% to 22% of patients with KTS. Although up to 30 KTS case reports with PE have been published,4,10,12-21 the exact mechanism underlying the hypercoagulability in vascular malformations remains unclear; 71
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however, coagulation activation may be attributed to dyspnea at inclusion time, defined as the perception the stagnation of blood within the distorted, enlarged of shortness of breath upon exertion or at rest. venous blood vessels.22-24 This could lead to a continuous formation of thrombi, resulting in recurrent PE, as Perfusion scintigraphy reported in several cases.14,16,18 Moreover, unresolved For the evaluation of PE, perfusion scintigraphy was recurrent PE, originating in the vascular malformations, performed in all patients following the 2004 guidelines may lead to chronic thromboembolism (CTE) or even of the Society of Nuclear Medicine. Q-scans were CTE pulmonary hypertension analyzed according to the (CTEPH) in patients with Modified Prospective InvestiCAPSULE SUMMARY KTS.14,16,18,21,25 Without early gation of PE Diagnosis30 criintervention, the prognosis of teria for the diagnosis of PE; A high incidence of venous CTEPH is poor and proporsubsequently, the images thromboembolism has been reported in tional to the degree of pulmowere also dichotomized in a patients with Klippel-Trenaunay nary hypertension; estimated normal or abnormal scan resyndrome, along with cases of belated survival rate at 5 years being sult. Perfusion defects with diagnosed chronic thromboembolism;10% in patients with a mean an evident extrapulmonary related pulmonary hypertension. pulmonary artery pressure cause, such as raised diaHowever, the prevalence of chronic greater than 50 mm Hg.26-28 phragm, were assigned as thromboembolism among patients with In our referral center for normal. All Q-scans were anKlippel-Trenaunay syndrome is CTEPH, we have encountered alyzed by experienced nuunknown. 4 patients with CTEPH and clear medicine physicians. The prevalence of chronic congenital vascular malformathromboembolism among 48 patients tions (two of whom had KTS) with Klippel-Trenaunay syndrome was over a 5-year period. In all CT scanning 4%, and higher than expected in a young patients, the diagnosis of In case of any abnorpatient population. CTEPH was made relatively malities on perfusion scinlate in the disease course. tigraphy, CT pulmonary Although echocardiography showed no Therefore, early detection angiography was performed signs of pulmonary hypertension in and diagnosis of chronic PE to detect signs of CTE, dethese patients, a low threshold for or CTEPH is crucial for optimal fined as residual perfusion screening remains appropriate. use of the available therapeuabnormalities after PE. CT tic modalities.27-29 pulmonary angiography However, although many alarming KTS case was performed using a multidetector row CT scanreports with CTE or CTEPH have been published, ner, according to standardized protocols, with the exact prevalence of CTE or CTEPH among standard contrast enhancement and acquisition of patients with KTS remains unknown. Therefore, we 0.5- to 1-mm sections. Axial images and coronal, performed a cross-sectional study in a wellsagittal, and oblique reconstructions were studied characterized cohort of Dutch patients with KTS to for signs of (chronic) PE. Acute PE was diagnosed if investigate the prevalence of chronic PE. contrast material outlined an intraluminal defect or if a vessel was totally occluded by low-attenuation METHODS material on at least two adjacent slices. Diagnostic Patients criteria for CTE were: (1) complete occlusion of a Adult patients ([21 years) from a wellvessel that is permanently smaller than pulmonary characterized cohort of Dutch patients with KTS arteries of the same order of branching; (2) periphwere eligible. Patients were examined using a seeral eccentric filling defect that makes an obtuse quential diagnostic workup including perfusion (Q) angle with the vessel wall; (3) contrast material scintigraphy, contrast-enhanced computed tomogflowing through thick-walled arteries with narrower raphy (CT), and echocardiography. The protocol lumen because of recanalization; and (4) the preswas approved by the medical ethical committee in ence of bands or a web in a contrast-filled artery.31 Supportive criteria for the presence of CTE(PH) the Academic Medical Center and all patients gave were: (1) presence of mosaic attenuation in the written informed consent. lung parenchyma; (2) dilatation of the main pulData on the history of VTE events, use of anticomonary artery; and (3) bronchial artery hypertroagulants, and comorbidity were collected and phy. In case of totally occluded vessels, signs of plasma D-dimer levels were measured in all patients. ‘‘ballooning’’ or ‘‘outpouching’’ were also The patients were questioned on the presence of d
d
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Abbreviations used: CI: CT: CTE: CTEPH: DVT: KTS: PE: SVT: VTE:
confidence interval computed tomography chronic thromboembolism chronic thromboembolic pulmonary hypertension deep vein thrombosis Klippel-Trenaunay syndrome pulmonary embolism superficial vein thrombosis venous thromboembolism
supportive of the diagnosis. All scans were analyzed by one radiologist, highly experienced in diagnosing CTEPH (O. M. v. D.). Transthoracic echocardiography In patients with CT scans suggestive of CTE, transthoracic echocardiography was performed as previously described32 to investigate signs of CTEPH. Pulmonary hypertension was defined by an echocardiographically determined systolic pulmonary artery pressure higher than 40 mm Hg, in agreement with current guidelines.33 D-dimer measurement As an indirect marker of coagulation and subsequent fibrinolysis, D-dimer levels were measured.34-36 For these measurements, blood samples were collected in citrated tubes and centrifuged for 15 minutes. Plasma was stored at e808C and D-dimer concentrations were determined with a quantitative enzyme-linked immunosorbent assay method (Asserachrom D-dimer, Diagnostica Stago, Asnieres, France). The cut-off for normality was 500 g/L. Statistics All numbers are medians with corresponding ranges, unless stated otherwise. Statistical analysis was performed by using software (SPSS 16.0.2, SPSS, Chicago, IL). The Mann-Whitney U test was used for nonparametric numeric data; Fisher exact test was used for categorical data.
RESULTS In total, 68 patients were eligible for inclusion in the study, of whom 20 patients did not participate because of refusal (n = 8), logistical reasons (n = 9), or other reasons (n = 3). Clinical characteristics of the 48 included patients are detailed in Table I. The mean age was 43 years (range 22-78 years) and 29 (60%) were female. In total, 25 patients (52%) had a documented history of VTE: 7 (14.6%) had a history of DVT, 3 (6.3%) of PE, and 23 (47.9%) of superficial vein thrombosis (SVT). There were 8 patients (16.7%) who had a history of either DVT or PE, two
Douma et al 73
of whom had had both (2 of 48, 4.2%). Seven patients (14.6%) had a bleeding history, including hematomas (n = 4), bleeding from venous blebs in the capillary malformation (n = 1), recurrent rectal blood loss (n = 1), and prolonged bleeding after surgery (n = 1). The excluded patients did not differ from those included: the mean age of the excluded patients was 40 years (range 22-69 years), 70% were female, 4 had a history of possible VTE (two SVT; one DVT; one PE), and 4 patients had shortness of breath, two of whom had normal Q-scan results made earlier for other reasons. Moreover, two patients with a history of objectively confirmed CTEPH21 had died before the start of this study and were therefore not among the 68 patients eligible for participation. Perfusion scan and CT scan All 48 patients underwent perfusion lung scanning. All scans were of adequate quality for analysis. Scan results were normal in 37 patients (77%). In the other 11 patients (23%), the scan showed diffuse irregularities in 3 patients and segmental and/or subsegmental defects in the other 8 patients. Patients with abnormalities on perfusion scintigraphy proceeded to CT scanning, with the exception of one patient who had moved abroad. This patient had several subsegmental defects on the perfusion scan, but did not have any reports of shortness of breath at that time. In the remaining 10 patients, the CT scan showed abnormalities in 3 patients, of whom two had definite signs of chronic PE (two of 48; 4.2%; 95% confidence interval [CI] 1.2%-14%). In both patients, the CT scan showed a dilated main pulmonary artery, acute tapering of pulmonary artery branches, and hypertrophy of bronchial arteries. The CT scan also showed occlusion of segmental lower lobe pulmonary arteries in patient 1 and webs in segmental branches in patient 2. These two patients therefore had CTE and a suspicion of CTEPH based on the CT scan. In the third patient, a dilated main pulmonary artery trunk was seen; however, definite signs of (chronic) PE were not present. Echocardiography In the 3 patients with abnormalities on CT scan, transthoracic echocardiography was performed. It demonstrated moderate dilatation of the right atrium in the first patient with CTE and moderate dilatation of the right ventricle in both patients with CTE. Echocardiography revealed no abnormalities in the third possible patient with CTE. Otherwise, echocardiography showed no further signs of
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Fig 1. Patient with Klippel-Trenaunay syndrome affecting right leg. Patient (Table II, patient 2) had previous episodes of superficial and deep vein thrombosis of right leg.
pulmonary hypertension; in particular, estimated systolic pulmonary artery pressure findings were normal in two patients and not measurable in the third (Table II). Clinical characteristics of the 3 patients with CT scan abnormalities are described in Table II. All 3 had a history of VTE. Two patients with signs of CTE on the CT scan had a history of either DVT or PE, for which one patient used maintenance therapy with an oral vitamin K antagonist. The second patient used naproxen twice weekly. All 3 patients reported shortness of breath. Interestingly, the third patient, in whom no definite signs of CTE were found, had chronic obstructive pulmonary disease, for which she used medication. The D-dimer was elevated in the two patients with CTE, but was within the normal limits in the third patient (Table II). Shortness of breath In total, 10 of the 48 patients reported shortness of breath of any kind. Patients with an abnormal Q-scan result more often (P \.0001) reported this compared with patients with normal Q-scan results: 7 of 11 (64%; 95% CI 35%-85%) and 3 of 37 (8.1%; 95% CI
2.8%-21%), respectively. Moreover, shortness of breath was more often reported by patients with a history of VTE (including DVT and PE) compared with patients with a history of SVT or patients without VTE in general: 6 of 8 patients (75%; 95% CI 41%-93%) with prior documented DVT/PE reported shortness of breath, compared with 3 of 17 patients (17.6%; 95% CI 6.2%-41%) with SVT, and one of 23 patients (4.3%; 95% CI 0.8%-21%) without known VTE of any kind, respectively (P \.001). The differences in shortness of breath between the groups could not be attributed to a difference in age (data not shown). Finally, patients with abnormalities on the Q-scan more often (P = .001) had a documented history of DVT or PE (6 of 11; 55%; 95% CI 28%-79%) compared with patients with a normal Q-scan result (two of 37; 5.4%; 95% CI 1.5%-18%). D-dimer test The median D-dimer level in the 48 included patients was 584 g/L, with a range of 122 to 25,131 g/L. The D-dimer was above the cut-off for normal value for exclusion of VTE (500 g/L) in 25 patients
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248 No dilation 34 No COPD medication Yes SVT of left arm CVLM with arteriovenous fistula of left arm, no involvement of musculature or bones F 3
48
24,488 Moderate dilation of right ventricle 29 Naproxen (twice weekly) CVLM, combined with hypertrophy of right leg; genitals and bladder were also involved (Fig 1)
SVT and DVT of right leg (lastly 1 y before)
Yes
Yes
2874
D-dimer, g/L Right cardiac changes*
Moderate dilation of right atrium and ventricle No datay Yes Vitamin K antagonists (maintenance) Yes
39
Among the patients with KTS included in this cross-sectional study, we found an observed prevalence of CTE of 4% (95% CI 1.2%-14%), whereas echocardiography showed no definite signs of pulmonary hypertension in the patients with CTE. These results appear reassuring after our previous report on two patients with KTS over a 5-year period referred to our hospital because of belatedly diagnosed CTEPH.21 Besides these two known and reported KTS-associated CTEPH cases, however, in the current study CTE was found in two additional patients,
M
DISCUSSION
2
(52%; 95% CI 39%-66%), and above 1000 g/L in 18 patients (38%; 95% CI 25%-52%). Patients with Q-scan abnormalities did not have higher D-dimer levels compared with patients with normal scan results (P = .634). The two patients with signs of chronic PE on the CT scan did not have higher D-dimer results compared with the other patients. Also, no difference was found between the D-dimer levels in patients with and without shortness of breath (P = .790) or with and without a history of VTE (P = .112).
CVLM, combined with hypertrophy Pulmonary in length and girth of left leg; embolism visceral organs were also affected (3.5 y before)
NSAIDs, Nonsteroidal anti-inflammatory drugs; VTE, venous thromboembolism. *In most patients parts of thorax also affected (n = 4). y In one patient thorax also affected, and in one patient face also affected. z All limbs, thorax, and face. x One side of body affected, including half of thorax, one upper and one lower limb; in one patient face was also affected. // Some patients had more than one type of venous thrombotic event.
47
(4.2) (10.4) (4.2) (6.9)
M
2 5 2 2
Signs of Estimated CTE sPAP, mm Hg*
(52.1) (47.9) (14.6) (6.2) (20.8)
Medication
25 23 7 3 10
Shortness of breath
(10.4) (70.8) (6.3) (6.3) (6.3)
History VTE
5 34 3 3 3
Location of KTS malformation
N = 48
43 (22-78) 29 (60.4)
Patient Sex Age, y
Age, y, median (range) Female sex, n (%) Localization, n (%) One upper limb* One lower limby Both lower limbs Diffusez Half of bodyx Previous VTE, n (%)// Total Superficial vein thrombosis Deep vein thrombosis Pulmonary embolism Dyspnea, n (%) Using anticoagulant medication, n (%) Vitamin K antagonists NSAIDs Acetylic acid Oral contraceptives (women only), n (%)
Table II. Characteristics of patients with Klippel-Trenaunay syndrome and abnormalities on computed tomographic scan findings
Characteristic
1
Table I. Baseline clinical characteristics of patients
COPD, Chronic obstructive pulmonary disease; CTE, chronic thromboembolism; CVLM, capillary-venous-lymphatic malformation; DVT, deep vein thrombosis; F, female; KTS, Klippel-Trenaunay syndrome; M, male; sPAP, systolic pulmonary artery pressure; SVT, superficial vein thrombosis; VTE, venous thromboembolism. *Measured with echocardiography. y No tricuspid regurgitation, therefore sPAP not measurable.
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which is still higher than expected in a relatively young patient population. A relatively large number of patients in this cohort had a history of VTE: 17% had a history of either DVT or PE and 52% had a history of SVT, DVT, and/or PE. With a mean age of 43 years, this frequency is higher than expected based on data derived from the general population,37,38 but in line with previous findings among patients with KTS.10 Moreover, the D-dimer level, a fibrin degradation product used as a marker for activation of the coagulation system, was above the cut-off for the exclusion of VTE (500 g/L) in half of the patients and above 1000 g/L (maximum of 25,131 g/L) in over a third of the patients. This is in support of the idea of an activated coagulation system in patients with KTS, as has also been reported in patients with venous malformations.34,35 Most likely, the increased D-dimer levels mainly reflect local fibrinolytic effects in and around the vascular malformations.23 The high prevalence of a history of VTE in our cohort suggests that this localized intravascular coagulation can eventually evolve to the formation of deep vein thrombi and consequently (recurrent) PE.21 Because there is overwhelming localized fibrinolytic activity in the vascular malformations, fibrinolytic activity elsewhere in the body will be obscured. This could explain the absence of a correlation between D-dimer levels and either Q-scan abnormalities or signs of chronic PE on the CT scan in our study. Because KTS is also associated with a high risk of bleeding, physicians are usually reluctant to administer long-term anticoagulation for (superficial) thrombosis.10,24 Another finding of interest was the high number of patients who reported shortness of breath. Patients with abnormal Q-scan results and/or patients with a documented history of DVT/PE reported this more frequently compared with patients with a normal Q-scan result or patients without a documented history of DVT/PE. Although two patients with shortness of breath showed signs of CTE on the CT scan, their symptoms appeared not attributable to CTEPH. Unfortunately, the origin of the symptoms was not determined, because this was beyond the scope of the current investigation. Two recent studies, however, found approximately half of the patients with prior PE to persistently report shortness of breath after the initial event, for which no explanation was found.39,40 The clear association between previous VTE and shortness of breath merits further investigation. Our study has several strengths and limitations. Although KTS is a rare disease, we were able to include a large sample of patients from a national
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cohort of patients with KTS. Not all patients from the cohort were able to participate in the study, two of whom had shortness of breath for which they were not further examined. Even though the cohort of patients with KTS is well characterized, and we know that these two patients did not have a documented history of VTE, we can not completely exclude that these patients had CTE(PH). Second, we did not perform echocardiography in all patients. The primary aim of the current study was to determine the prevalence of CTE; in addition, we studied whether patients with signs of CTE on the CT scan experienced CTE-related pulmonary hypertension. Third, we performed all echocardiographic measurements in resting state. Therefore, we cannot completely exclude the possibility that exercise-induced CTEPH may have been present in the patients with CTE. However, the meaning of exercise-induced CTEPH is currently unclear and its practical implications are very limited.26 In conclusion, despite the apparent frequency and severity of the earlier reported cases of CTEPH, in this well-defined Dutch KTS cohort, the prevalence of CTE and CTE-associated pulmonary hypertension (CTEPH) in particular was less alarming than previously assumed. Although a large proportion of patients with KTS had a documented history of VTE and high D-dimer levels, in relatively few patients CTE could be documented; moreover, we did not find definite signs of CTEPH in any of the patients in this cohort. Based on the current findings, we suggest that the indication for screening for CTE(PH) among patients with KTS is limited. Nevertheless, given the severity of cases previously reported and the high prevalence of VTE among patients with KTS, awareness and a low threshold for CTE(PH) screening seems appropriate for patients with KTS who present with shortness of breath. REFERENCES 1. Oduber CE, van der Horst CM, Hennekam RC. KlippelTrenaunay syndrome: diagnostic criteria and hypothesis on etiology. Ann Plast Surg 2008;60:217-23. 2. Klippel M, Trenaunay P. Memoires originaux: du noevus variqueux osteohypertrophique. Arch Gen Med 1900;Tome III:641-72. 3. Mulliken JB. Combined vascular malformations. In: Mulliken JB, Young AE, editors. Vascular birthmarks: hemangiomas and malformations. Philadelphia: WB Saunders Co; 1988. p. 246-64. 4. Jacob AG, Driscoll DJ, Shaughnessy WJ, Stanson AW, Clay RP, Gloviczki P. Klippel-Trenaunay syndrome: spectrum and management. Mayo Clin Proc 1998;73:28-36. 5. Cohen MM Jr. Klippel-Trenaunay syndrome. Am J Med Genet 2000;93:171-5. 6. Lorda-Sanchez I, Prieto L, Rodriguez-Pinilla E, Martinez-Frias ML. Increased parental age and number of pregnancies in
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thromboembolic pulmonary hypertension. Eur Respir J 2009; 33:332-8. Riedel M, Stanek V, Widimsky J, Prerovsky I. Long-term followup of patients with pulmonary thromboembolism: late prognosis and evolution of hemodynamic and respiratory data. Chest 1982;81:151-8. Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001;345: 1465-72. Jamieson SW. Historical perspective: surgery for chronic thromboembolic disease. Semin Thorac Cardiovasc Surg 2006;18:218-22. Bresser P, Pepke-Zaba J, Jais X, Humbert M, Hoeper MM. Medical therapies for chronic thromboembolic pulmonary hypertension: an evolving treatment paradigm. Proc Am Thorac Soc 2006;3:594-600. Gottschalk A, Sostman HD, Coleman RE, Juni JE, Thrall J, McKusick KA, et al. Ventilation-perfusion scintigraphy in the PIOPED study, part II: evaluation of the scintigraphic criteria and interpretations. J Nucl Med 1993;34:1119-26. Wittram C. How I do it: CT pulmonary angiography. AJR Am J Roentgenol 2007;188:1255-61. Hardziyenka M, Reesink HJ, Bouma BJ, de Bruin-Bon HA, Campian ME, Tanck MW, et al. A novel echocardiographic predictor of in-hospital mortality and mid-term hemodynamic improvement after pulmonary endarterectomy for chronic thrombo-embolic pulmonary hypertension. Eur Heart J 2007; 28:842-9. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society Inc; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009; 53:1573-619. Mazoyer E, Enjolras O, Bisdorff A, Perdu J, Wassef M, Drouet L. Coagulation disorders in patients with venous malformation of the limbs and trunk: a case series of 118 patients. Arch Dermatol 2008;144:861-7. Dompmartin A, Acher A, Thibon P, Tourbach S, Hermans C, Deneys V, et al. Association of localized intravascular coagulopathy with venous malformations. Arch Dermatol 2008;144: 873-7. Dompmartin A, Ballieux F, Thibon P, Lequerrec A, Hermans C, Clapuyt P, et al. Elevated D-dimer level in the differential diagnosis of venous malformations. Arch Dermatol 2009;145: 1239-44. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ III. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585-93. Oger E. Incidence of venous thromboembolism: a communitybased study in Western France; EPI-GETBP study group, Groupe d’Etude de la Thrombose de Bretagne Occidentale. Thromb Haemost 2000;83:657-60. Klok FA, Tijmensen JE, Haeck ML, van Kralingen KW, Huisman MV. Persistent dyspnea complaints at long-term follow-up after an episode of acute pulmonary embolism: results of a questionnaire. Eur J Intern Med 2008;19:625-9. Surie S, Gibson NS, Gerdes VE, Bouma BJ, van Eck-Smit BL, Buller HR, et al. Active search for chronic thromboembolic pulmonary hypertension does not appear indicated after acute pulmonary embolism. Thromb Res 2010;125:e202-5.
From the Departments of Vascular Medicine,a Plastic, Reconstructive, and Hand Surgery,b Radiology,c Nuclear Medicine,d Experimental Vascular Medicine,e Internal Medicine and Hematology,f Cardiology,g and Respiratory Medicine,h Academic Medical Center; Department of Internal Medicine, Slotervaart Hospitali; and Department of Respiratory Medicine, Onze Lieve Vrouwe Gasthuis.j *These authors contributed equally. Funding sources: None. Conflicts of interest: None declared. Accepted for publication December 4, 2010. Reprint requests: Renee A. Douma, MD, Department of Vascular Medicine, Academic Medical Center, Suite F4-143, Meibergdreef 9, PO Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: [email protected]. Published online May 16, 2011. 0190-9622/$36.00 Ó 2011 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.12.002
K
lippel-Trenaunay syndrome (KTS) is characterized by a combination of capillary, venous, and lymphatic malformations, and a localized disturbed growth of bone and/or soft tissues (Fig 1).1-5 The syndrome occurs in all ethnic groups, with an estimated prevalence of 1/20,000 to 1/100,000 live births.6-8 Clinical presentation may vary from being asymptomatic to developing potentially life-threatening complications, such as deep vein thrombosis (DVT), pulmonary embolism (PE), and recurrent bleeding.4,9-11 Venous thromboembolism (VTE) has been reported in 8% to 22% of patients with KTS. Although up to 30 KTS case reports with PE have been published,4,10,12-21 the exact mechanism underlying the hypercoagulability in vascular malformations remains unclear; 71
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however, coagulation activation may be attributed to dyspnea at inclusion time, defined as the perception the stagnation of blood within the distorted, enlarged of shortness of breath upon exertion or at rest. venous blood vessels.22-24 This could lead to a continuous formation of thrombi, resulting in recurrent PE, as Perfusion scintigraphy reported in several cases.14,16,18 Moreover, unresolved For the evaluation of PE, perfusion scintigraphy was recurrent PE, originating in the vascular malformations, performed in all patients following the 2004 guidelines may lead to chronic thromboembolism (CTE) or even of the Society of Nuclear Medicine. Q-scans were CTE pulmonary hypertension analyzed according to the (CTEPH) in patients with Modified Prospective InvestiCAPSULE SUMMARY KTS.14,16,18,21,25 Without early gation of PE Diagnosis30 criintervention, the prognosis of teria for the diagnosis of PE; A high incidence of venous CTEPH is poor and proporsubsequently, the images thromboembolism has been reported in tional to the degree of pulmowere also dichotomized in a patients with Klippel-Trenaunay nary hypertension; estimated normal or abnormal scan resyndrome, along with cases of belated survival rate at 5 years being sult. Perfusion defects with diagnosed chronic thromboembolism;10% in patients with a mean an evident extrapulmonary related pulmonary hypertension. pulmonary artery pressure cause, such as raised diaHowever, the prevalence of chronic greater than 50 mm Hg.26-28 phragm, were assigned as thromboembolism among patients with In our referral center for normal. All Q-scans were anKlippel-Trenaunay syndrome is CTEPH, we have encountered alyzed by experienced nuunknown. 4 patients with CTEPH and clear medicine physicians. The prevalence of chronic congenital vascular malformathromboembolism among 48 patients tions (two of whom had KTS) with Klippel-Trenaunay syndrome was over a 5-year period. In all CT scanning 4%, and higher than expected in a young patients, the diagnosis of In case of any abnorpatient population. CTEPH was made relatively malities on perfusion scinlate in the disease course. tigraphy, CT pulmonary Although echocardiography showed no Therefore, early detection angiography was performed signs of pulmonary hypertension in and diagnosis of chronic PE to detect signs of CTE, dethese patients, a low threshold for or CTEPH is crucial for optimal fined as residual perfusion screening remains appropriate. use of the available therapeuabnormalities after PE. CT tic modalities.27-29 pulmonary angiography However, although many alarming KTS case was performed using a multidetector row CT scanreports with CTE or CTEPH have been published, ner, according to standardized protocols, with the exact prevalence of CTE or CTEPH among standard contrast enhancement and acquisition of patients with KTS remains unknown. Therefore, we 0.5- to 1-mm sections. Axial images and coronal, performed a cross-sectional study in a wellsagittal, and oblique reconstructions were studied characterized cohort of Dutch patients with KTS to for signs of (chronic) PE. Acute PE was diagnosed if investigate the prevalence of chronic PE. contrast material outlined an intraluminal defect or if a vessel was totally occluded by low-attenuation METHODS material on at least two adjacent slices. Diagnostic Patients criteria for CTE were: (1) complete occlusion of a Adult patients ([21 years) from a wellvessel that is permanently smaller than pulmonary characterized cohort of Dutch patients with KTS arteries of the same order of branching; (2) periphwere eligible. Patients were examined using a seeral eccentric filling defect that makes an obtuse quential diagnostic workup including perfusion (Q) angle with the vessel wall; (3) contrast material scintigraphy, contrast-enhanced computed tomogflowing through thick-walled arteries with narrower raphy (CT), and echocardiography. The protocol lumen because of recanalization; and (4) the preswas approved by the medical ethical committee in ence of bands or a web in a contrast-filled artery.31 Supportive criteria for the presence of CTE(PH) the Academic Medical Center and all patients gave were: (1) presence of mosaic attenuation in the written informed consent. lung parenchyma; (2) dilatation of the main pulData on the history of VTE events, use of anticomonary artery; and (3) bronchial artery hypertroagulants, and comorbidity were collected and phy. In case of totally occluded vessels, signs of plasma D-dimer levels were measured in all patients. ‘‘ballooning’’ or ‘‘outpouching’’ were also The patients were questioned on the presence of d
d
d
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Abbreviations used: CI: CT: CTE: CTEPH: DVT: KTS: PE: SVT: VTE:
confidence interval computed tomography chronic thromboembolism chronic thromboembolic pulmonary hypertension deep vein thrombosis Klippel-Trenaunay syndrome pulmonary embolism superficial vein thrombosis venous thromboembolism
supportive of the diagnosis. All scans were analyzed by one radiologist, highly experienced in diagnosing CTEPH (O. M. v. D.). Transthoracic echocardiography In patients with CT scans suggestive of CTE, transthoracic echocardiography was performed as previously described32 to investigate signs of CTEPH. Pulmonary hypertension was defined by an echocardiographically determined systolic pulmonary artery pressure higher than 40 mm Hg, in agreement with current guidelines.33 D-dimer measurement As an indirect marker of coagulation and subsequent fibrinolysis, D-dimer levels were measured.34-36 For these measurements, blood samples were collected in citrated tubes and centrifuged for 15 minutes. Plasma was stored at e808C and D-dimer concentrations were determined with a quantitative enzyme-linked immunosorbent assay method (Asserachrom D-dimer, Diagnostica Stago, Asnieres, France). The cut-off for normality was 500 g/L. Statistics All numbers are medians with corresponding ranges, unless stated otherwise. Statistical analysis was performed by using software (SPSS 16.0.2, SPSS, Chicago, IL). The Mann-Whitney U test was used for nonparametric numeric data; Fisher exact test was used for categorical data.
RESULTS In total, 68 patients were eligible for inclusion in the study, of whom 20 patients did not participate because of refusal (n = 8), logistical reasons (n = 9), or other reasons (n = 3). Clinical characteristics of the 48 included patients are detailed in Table I. The mean age was 43 years (range 22-78 years) and 29 (60%) were female. In total, 25 patients (52%) had a documented history of VTE: 7 (14.6%) had a history of DVT, 3 (6.3%) of PE, and 23 (47.9%) of superficial vein thrombosis (SVT). There were 8 patients (16.7%) who had a history of either DVT or PE, two
Douma et al 73
of whom had had both (2 of 48, 4.2%). Seven patients (14.6%) had a bleeding history, including hematomas (n = 4), bleeding from venous blebs in the capillary malformation (n = 1), recurrent rectal blood loss (n = 1), and prolonged bleeding after surgery (n = 1). The excluded patients did not differ from those included: the mean age of the excluded patients was 40 years (range 22-69 years), 70% were female, 4 had a history of possible VTE (two SVT; one DVT; one PE), and 4 patients had shortness of breath, two of whom had normal Q-scan results made earlier for other reasons. Moreover, two patients with a history of objectively confirmed CTEPH21 had died before the start of this study and were therefore not among the 68 patients eligible for participation. Perfusion scan and CT scan All 48 patients underwent perfusion lung scanning. All scans were of adequate quality for analysis. Scan results were normal in 37 patients (77%). In the other 11 patients (23%), the scan showed diffuse irregularities in 3 patients and segmental and/or subsegmental defects in the other 8 patients. Patients with abnormalities on perfusion scintigraphy proceeded to CT scanning, with the exception of one patient who had moved abroad. This patient had several subsegmental defects on the perfusion scan, but did not have any reports of shortness of breath at that time. In the remaining 10 patients, the CT scan showed abnormalities in 3 patients, of whom two had definite signs of chronic PE (two of 48; 4.2%; 95% confidence interval [CI] 1.2%-14%). In both patients, the CT scan showed a dilated main pulmonary artery, acute tapering of pulmonary artery branches, and hypertrophy of bronchial arteries. The CT scan also showed occlusion of segmental lower lobe pulmonary arteries in patient 1 and webs in segmental branches in patient 2. These two patients therefore had CTE and a suspicion of CTEPH based on the CT scan. In the third patient, a dilated main pulmonary artery trunk was seen; however, definite signs of (chronic) PE were not present. Echocardiography In the 3 patients with abnormalities on CT scan, transthoracic echocardiography was performed. It demonstrated moderate dilatation of the right atrium in the first patient with CTE and moderate dilatation of the right ventricle in both patients with CTE. Echocardiography revealed no abnormalities in the third possible patient with CTE. Otherwise, echocardiography showed no further signs of
74 Douma et al
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Fig 1. Patient with Klippel-Trenaunay syndrome affecting right leg. Patient (Table II, patient 2) had previous episodes of superficial and deep vein thrombosis of right leg.
pulmonary hypertension; in particular, estimated systolic pulmonary artery pressure findings were normal in two patients and not measurable in the third (Table II). Clinical characteristics of the 3 patients with CT scan abnormalities are described in Table II. All 3 had a history of VTE. Two patients with signs of CTE on the CT scan had a history of either DVT or PE, for which one patient used maintenance therapy with an oral vitamin K antagonist. The second patient used naproxen twice weekly. All 3 patients reported shortness of breath. Interestingly, the third patient, in whom no definite signs of CTE were found, had chronic obstructive pulmonary disease, for which she used medication. The D-dimer was elevated in the two patients with CTE, but was within the normal limits in the third patient (Table II). Shortness of breath In total, 10 of the 48 patients reported shortness of breath of any kind. Patients with an abnormal Q-scan result more often (P \.0001) reported this compared with patients with normal Q-scan results: 7 of 11 (64%; 95% CI 35%-85%) and 3 of 37 (8.1%; 95% CI
2.8%-21%), respectively. Moreover, shortness of breath was more often reported by patients with a history of VTE (including DVT and PE) compared with patients with a history of SVT or patients without VTE in general: 6 of 8 patients (75%; 95% CI 41%-93%) with prior documented DVT/PE reported shortness of breath, compared with 3 of 17 patients (17.6%; 95% CI 6.2%-41%) with SVT, and one of 23 patients (4.3%; 95% CI 0.8%-21%) without known VTE of any kind, respectively (P \.001). The differences in shortness of breath between the groups could not be attributed to a difference in age (data not shown). Finally, patients with abnormalities on the Q-scan more often (P = .001) had a documented history of DVT or PE (6 of 11; 55%; 95% CI 28%-79%) compared with patients with a normal Q-scan result (two of 37; 5.4%; 95% CI 1.5%-18%). D-dimer test The median D-dimer level in the 48 included patients was 584 g/L, with a range of 122 to 25,131 g/L. The D-dimer was above the cut-off for normal value for exclusion of VTE (500 g/L) in 25 patients
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248 No dilation 34 No COPD medication Yes SVT of left arm CVLM with arteriovenous fistula of left arm, no involvement of musculature or bones F 3
48
24,488 Moderate dilation of right ventricle 29 Naproxen (twice weekly) CVLM, combined with hypertrophy of right leg; genitals and bladder were also involved (Fig 1)
SVT and DVT of right leg (lastly 1 y before)
Yes
Yes
2874
D-dimer, g/L Right cardiac changes*
Moderate dilation of right atrium and ventricle No datay Yes Vitamin K antagonists (maintenance) Yes
39
Among the patients with KTS included in this cross-sectional study, we found an observed prevalence of CTE of 4% (95% CI 1.2%-14%), whereas echocardiography showed no definite signs of pulmonary hypertension in the patients with CTE. These results appear reassuring after our previous report on two patients with KTS over a 5-year period referred to our hospital because of belatedly diagnosed CTEPH.21 Besides these two known and reported KTS-associated CTEPH cases, however, in the current study CTE was found in two additional patients,
M
DISCUSSION
2
(52%; 95% CI 39%-66%), and above 1000 g/L in 18 patients (38%; 95% CI 25%-52%). Patients with Q-scan abnormalities did not have higher D-dimer levels compared with patients with normal scan results (P = .634). The two patients with signs of chronic PE on the CT scan did not have higher D-dimer results compared with the other patients. Also, no difference was found between the D-dimer levels in patients with and without shortness of breath (P = .790) or with and without a history of VTE (P = .112).
CVLM, combined with hypertrophy Pulmonary in length and girth of left leg; embolism visceral organs were also affected (3.5 y before)
NSAIDs, Nonsteroidal anti-inflammatory drugs; VTE, venous thromboembolism. *In most patients parts of thorax also affected (n = 4). y In one patient thorax also affected, and in one patient face also affected. z All limbs, thorax, and face. x One side of body affected, including half of thorax, one upper and one lower limb; in one patient face was also affected. // Some patients had more than one type of venous thrombotic event.
47
(4.2) (10.4) (4.2) (6.9)
M
2 5 2 2
Signs of Estimated CTE sPAP, mm Hg*
(52.1) (47.9) (14.6) (6.2) (20.8)
Medication
25 23 7 3 10
Shortness of breath
(10.4) (70.8) (6.3) (6.3) (6.3)
History VTE
5 34 3 3 3
Location of KTS malformation
N = 48
43 (22-78) 29 (60.4)
Patient Sex Age, y
Age, y, median (range) Female sex, n (%) Localization, n (%) One upper limb* One lower limby Both lower limbs Diffusez Half of bodyx Previous VTE, n (%)// Total Superficial vein thrombosis Deep vein thrombosis Pulmonary embolism Dyspnea, n (%) Using anticoagulant medication, n (%) Vitamin K antagonists NSAIDs Acetylic acid Oral contraceptives (women only), n (%)
Table II. Characteristics of patients with Klippel-Trenaunay syndrome and abnormalities on computed tomographic scan findings
Characteristic
1
Table I. Baseline clinical characteristics of patients
COPD, Chronic obstructive pulmonary disease; CTE, chronic thromboembolism; CVLM, capillary-venous-lymphatic malformation; DVT, deep vein thrombosis; F, female; KTS, Klippel-Trenaunay syndrome; M, male; sPAP, systolic pulmonary artery pressure; SVT, superficial vein thrombosis; VTE, venous thromboembolism. *Measured with echocardiography. y No tricuspid regurgitation, therefore sPAP not measurable.
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which is still higher than expected in a relatively young patient population. A relatively large number of patients in this cohort had a history of VTE: 17% had a history of either DVT or PE and 52% had a history of SVT, DVT, and/or PE. With a mean age of 43 years, this frequency is higher than expected based on data derived from the general population,37,38 but in line with previous findings among patients with KTS.10 Moreover, the D-dimer level, a fibrin degradation product used as a marker for activation of the coagulation system, was above the cut-off for the exclusion of VTE (500 g/L) in half of the patients and above 1000 g/L (maximum of 25,131 g/L) in over a third of the patients. This is in support of the idea of an activated coagulation system in patients with KTS, as has also been reported in patients with venous malformations.34,35 Most likely, the increased D-dimer levels mainly reflect local fibrinolytic effects in and around the vascular malformations.23 The high prevalence of a history of VTE in our cohort suggests that this localized intravascular coagulation can eventually evolve to the formation of deep vein thrombi and consequently (recurrent) PE.21 Because there is overwhelming localized fibrinolytic activity in the vascular malformations, fibrinolytic activity elsewhere in the body will be obscured. This could explain the absence of a correlation between D-dimer levels and either Q-scan abnormalities or signs of chronic PE on the CT scan in our study. Because KTS is also associated with a high risk of bleeding, physicians are usually reluctant to administer long-term anticoagulation for (superficial) thrombosis.10,24 Another finding of interest was the high number of patients who reported shortness of breath. Patients with abnormal Q-scan results and/or patients with a documented history of DVT/PE reported this more frequently compared with patients with a normal Q-scan result or patients without a documented history of DVT/PE. Although two patients with shortness of breath showed signs of CTE on the CT scan, their symptoms appeared not attributable to CTEPH. Unfortunately, the origin of the symptoms was not determined, because this was beyond the scope of the current investigation. Two recent studies, however, found approximately half of the patients with prior PE to persistently report shortness of breath after the initial event, for which no explanation was found.39,40 The clear association between previous VTE and shortness of breath merits further investigation. Our study has several strengths and limitations. Although KTS is a rare disease, we were able to include a large sample of patients from a national
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cohort of patients with KTS. Not all patients from the cohort were able to participate in the study, two of whom had shortness of breath for which they were not further examined. Even though the cohort of patients with KTS is well characterized, and we know that these two patients did not have a documented history of VTE, we can not completely exclude that these patients had CTE(PH). Second, we did not perform echocardiography in all patients. The primary aim of the current study was to determine the prevalence of CTE; in addition, we studied whether patients with signs of CTE on the CT scan experienced CTE-related pulmonary hypertension. Third, we performed all echocardiographic measurements in resting state. Therefore, we cannot completely exclude the possibility that exercise-induced CTEPH may have been present in the patients with CTE. However, the meaning of exercise-induced CTEPH is currently unclear and its practical implications are very limited.26 In conclusion, despite the apparent frequency and severity of the earlier reported cases of CTEPH, in this well-defined Dutch KTS cohort, the prevalence of CTE and CTE-associated pulmonary hypertension (CTEPH) in particular was less alarming than previously assumed. Although a large proportion of patients with KTS had a documented history of VTE and high D-dimer levels, in relatively few patients CTE could be documented; moreover, we did not find definite signs of CTEPH in any of the patients in this cohort. Based on the current findings, we suggest that the indication for screening for CTE(PH) among patients with KTS is limited. Nevertheless, given the severity of cases previously reported and the high prevalence of VTE among patients with KTS, awareness and a low threshold for CTE(PH) screening seems appropriate for patients with KTS who present with shortness of breath. REFERENCES 1. Oduber CE, van der Horst CM, Hennekam RC. KlippelTrenaunay syndrome: diagnostic criteria and hypothesis on etiology. Ann Plast Surg 2008;60:217-23. 2. Klippel M, Trenaunay P. Memoires originaux: du noevus variqueux osteohypertrophique. Arch Gen Med 1900;Tome III:641-72. 3. Mulliken JB. Combined vascular malformations. In: Mulliken JB, Young AE, editors. Vascular birthmarks: hemangiomas and malformations. Philadelphia: WB Saunders Co; 1988. p. 246-64. 4. Jacob AG, Driscoll DJ, Shaughnessy WJ, Stanson AW, Clay RP, Gloviczki P. Klippel-Trenaunay syndrome: spectrum and management. Mayo Clin Proc 1998;73:28-36. 5. Cohen MM Jr. Klippel-Trenaunay syndrome. Am J Med Genet 2000;93:171-5. 6. Lorda-Sanchez I, Prieto L, Rodriguez-Pinilla E, Martinez-Frias ML. Increased parental age and number of pregnancies in
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