Pulmonary Arterial Hypertension in Patients with Slow-Flow Vascular Malformations

STUDY Pulmonary Arterial Hypertension in Patients With Slow-Flow Vascular Malformations

Moise´s Rodrı´guez-Man˜ero, MD; Leyre Aguado, MD; Pedro Redondo, MD, PhD

Objective: To determine the prevalence of pulmonary Results: Patients had a mean (SD) PASP that was sig- arterial hypertension in asymptomatic patients with 2 nificantly higher than that of healthy controls (42.16 types of extensive slow-flow vascular malformations: ex- [8.49] mm Hg in patients vs 27.69 [6.54] mm Hg in tensive venous malformations or Klippel-Tre´naunay syn- healthy controls; PϽ.001). No significant differences in drome (KTS). PASP were found between patients with KTS and patients with venous malformations (P=.80). We ob- Design: Case-control. served significant differences in the mean (SD) levels of vWF between patients and healthy controls (124.41% Setting: Multidisciplinary center for vascular anoma- [52.28%] in patients vs 92.69% [28.92%] in controls; lies. P=.01) and also in levels of D-dimer (1032.99 [1367.0] ng/mL in patients vs 102.97 [29.39] ng/mL in healthy Patients: A consecutive sample of 32 patients with slow- controls; PϽ.001). There was a moderate positive cor- flow vascular malformations of at least 15% of the body surface was identified retrospectively and matched by age relation between levels of vWF and levels of PASP (r=0.42; and sex with 32 healthy controls. P=.001) and a high positive correlation between D- dimer and PASP (r=0.52; PϽ.001) Interventions: Standard 2-dimensional transthoracic Doppler echocardiography. Venous samples were ob- Conclusions: The presence of pulmonary arterial hy- tained the same day that echocardiography was per- pertension in patients with extensive slow-flow vascu- formed. lar malformations is not an isolated feature but is rela- tively frequent. Levels of D-dimer correlate with PASP Main Outcome Measures: Pulmonary artery sys- in these patients tolic pressure (PASP) was determined. Levels of D- dimer, fibrinogen, and von Willebrand factor (vWF) in plasma were measured. Arch Dermatol. 2010;146(12):1347-1352

LOW-FLOW VASCULAR MALFOR- factors inside the malformation due to ve- mations are divided into venous stasis, resulting in the formation of nous, lymphatic, and com- multiple phleboliths. Elevated D-dimer lev- bined malformations such as els are highly specific for venous malfor- Klippel-Tre´naunay syndrome mations (or the venous component in com- (KTS).S Venous malformations are ectatic bined malformations).6,7 vessels that are morphologically and histo- logically similar to veins but deficient in For editorial comment smooth muscle.1 Klippel-Tre´naunay syn- see page 1416 drome is characterized by venous, lymphatic, and capillary malformations (port- The main complication of KTS is wine stain); skeletal hypertrophy; and thrombophlebitis, which occurs in 20% to increased soft tissue in 1 or more limbs.2 Co- 45% of patients8 and leads to pulmonary agulation disorders, which have been re- embolism in 4% to 25% of cases.9 Throm- ported in patients with venous malforma- boembolic events can cause chronic tions and KTS,3,4 can produce hemorrhage thromboembolic pulmonary hyperten- Author Affiliations: and thrombosis. The magnitude of the co- sion (CTEPH), which has also been de- Departments of Cardiology agulopathy correlates with the severity of scribed as a complication of pure venous (Dr Rodrı´guez-Man˜ ero) and the malformation5 and is a localized intra- malformations, probably due to throm- Dermatology, Unit of Vascular 10 Malformations (Drs Aguado vascular coagulation (LIC), which differs boembolic events. CTEPH is a type of and Redondo), University from the diffuse intravascular coagulation pulmonary arterial hypertension (PAH). Clinic of Navarra, Pamplona, of Kasabach-Merritt syndrome. LIC con- There are some reports of PAH in patients Spain. sists of a local consumption of coagulation with vascular malformations who had symp-

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Assessed for eligibility: 63 32 VM, 43; KTS, 18; LM, 2

Excluded: 32 (LM, 2; VM, 29) (because the malformations were not extensive)

Included: 32 32 VM, 14; KTS, 18

Echocardiogram: 32 32

5 Refused to undergo analysis. 3 Refused to D-dimer was not analyzed in undergo 3 patients because of an error. analysis

Analysis of: • D-dimer 24 29 • Fibrinogen 27 29 • vWF 27 29

Figure 1. Two patients. A, A 6-year-old patient with extensive venous Figure 2. Flowchart. KTS indicates Klippel-Tre´naunay syndrome; malformation involving right buttock and lower limb. B, A 26-year-old man LM, lymphatic malformation; VM, venous malformation; WF, von Willebrand with Klippel-Tre´naunay syndrome with port-wine stain of geographic factor. morphology and dark red-purple color, and extensive venous malformation (several phlebectasias in the thigh and leg). and the specificity is 60% to 98%.17 Pulmonary arterial systolic pressure (PASP) (determined by the velocity of tricuspid toms such as dyspnea10-15 This study examines the preva- regurgitation by continuous wave Doppler in the echocardio- lence of PAH in asymptomatic patients with slow-flow vas- gram) was measured. We considered PASP values of 50 mm Hg cular malformations. or higher to be pathological. Values of 37 to 50 mm Hg were considered borderline, and values equal to or lower than 36 mm Hg were considered normal.18,19 METHODS Venous samples were drawn from the cubital vein the same day as the echocardiography study. Plasma was removed and Sample patients had extensive slow-flow vascular malforma- stored at −80°C until analysis. To determine vWF levels, we tions (venous or combined malformations such as KTS) and used STA LIATEST vWF reagent (Diagnostica Stago/Roche, did not have cardiovascular risk factors, including variables that Asnières, France) and the STA Compact analyzer (Stago/ could be related to PAH, or a history of symptomatic pulmo- Roche). To determine levels of fibrinogen, we used Multifi- nary embolism. All patients were asymptomatic, without any bern U (Siemens Healthcare diagnostics products, Marburg, Ger- signs or symptoms of heart failure. A vascular malformation many) and the BCS XP Siemens system. We measured the levels was considered to be extensive if it involved at least 15% of the of D-dimer, using D-dimer PLUS (Dade Behring Marburg GmbH, patient’s body surface area (equivalent to Ն1 complete lower Marburg, Germany) and the BCS XP Siemens system. extremity) (Figure 1). All venous lesions had infiltrated the muscular plane and involved the skin and subcutaneous cell STATISTICAL ANALYSIS tissue.16 A patient was diagnosed as having KTS when soft- tissue and/or bony hypertrophy, port-wine stain, and venous All results were analyzed using SPSS statistical software (ver- varicosities were all present. The exclusion criteria were small sion 15.0; SPSS Inc, Chicago, Illinois). In all cases, we consid- or intermediate slow-flow malformations, high-flow malfor- ered 2-sided P Ͻ.05 to be statistically significant. Continuous mations, or the presence of cardiovascular disease. variables were compared using t test or with Mann-Whitney The diagnosis was made by clinical examination and con- test (when nonparametric tests were necessary). Correlations firmed by Doppler ultrasonography when necessary Thirty- between continuous variables were examined using Spearman two healthy controls, relatives and friends of the authors, with rank correlation. To determine if there were differences in D- no vascular disorder of any kind and without cardiovascular dimer values among groups of patients with normal, border- risk factors, were also included. They were matched by age and line, and pathological PASP, we used the Kruskal-Wallis test sex with the patients, and they were tested in the same period and then made post hoc paired comparisons using Bonferroni- as the patients. The study was approved by the ethics commit- corrected Mann-Whitney tests. tee of the University Clinic of Navarra (Pamplona, Spain), and written informed consent was obtained from all participants. RESULTS PROCEDURES SAMPLE CHARACTERISTICS Patients underwent a standard 12-lead electrocardiogram (ECG) and transthoracic Doppler echocardiography (TTDE). The sen- Sixty-three consecutive patients with slow-flow vascular sitivity of TTDE to establish the presence of PAH is 79% to 100%, malformations referred to our multidisciplinary center for

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 vascular anomalies in Pamplona were evaluated from 2008 through 2009. Twenty-nine patients with venous malfor- Table 1. Data of Patients and Controls mations and 2 with lymphatic malformations were excluded because they did not meet the criteria regarding the Patients Controls Variablea (n=32) (n=32) P Value extent of the lesions (Figure 2). All patients with KTS were also included. A total of 32 patients (15 women and 17 men; Sex Ͼ.99 mean age, 27 years [range, 3-62 years]) fulfilling the cri- Male 17 17 Female 15 15 teria of extensive slow-flow malformations were included Age, mean, y 27 (14) 31 (13) .30 in this retrospective analysis. Eighteen patients had KTS, PASP level, mm Hg 42.16 (8.49) 27.69 (6.54) Ͻ.001 and 14 had extensive venous malformations. Clinical char- Fibrinogen level, mg/dL 260.81 (84.62) 257.93 (51.32) .55 acteristics of subjects and controls are compared (Table 1), vWF, % 124.41 (52.28) 92.69 (28.92) .01 and patients with venous malformations and KTS are de- D-dimer level, ng/mL 1032.99 (1367.0) 102.97 (29.39) Ͻ.001 scribed herein (Table 2). Abbreviations: PASP, pulmonary artery systolic pressure; vWF, von Willebrand factor. CARDIOLOGIC FINDINGS SI conversion factor: To convert fibrinogen to micromoles per liter, multiply by 0.0294. Findings from all ECGs were normal except for 1 pa- a Data are given as mean (SD) except where noted. tient with KTS who presented with left bundle branch block. In the echocardiogram, 7 patients (22%) showed all, there was a high positive correlation between D- PASP values of 50 mm Hg or higher (pathological), 16 dimer and PASP (r=0.52; PϽ.001). There were signifi- (50%) showed values of 37 to 50 mm Hg (borderline), cant differences in the mean (SD) vWF in plasma between and 9 (28%) had PASP equal to or lower than 36 mm Hg controls (92.69% [28.92%]) and patients (124.41% (normal). None of the healthy controls showed PASP val- [52.28%]; P=.01). There were no differences in levels of ues of 50 mm Hg or higher, 2 (6%) had values of 37 and vWF between patients with KTS and those in the ve- 50 mm Hg (borderline), and 30 (94%) had PASP equal nous malformation group (P=.27). There was a moder- to or lower than 36 mm Hg (normal). ate positive correlation between levels of vWF and lev- Patients had a mean (SD) pulmonary pressure that was els of PASP (r=0.42; P=.001). There was no significant significantly higher than that of healthy controls (42.16 difference in levels of fibrinogen between patients (260.81 [8.49] mm Hg in patients vs 27.69 [6.54] mm Hg in con- [84.62] mg/dL) and healthy controls (257.93 [51.32] mg/ trols; PϽ.001) (Figure 3). There were no differences dL; P=.55). (To convert fibrinogen to micromoles per in other echocardiographic measures. No differences were liter, multiply by 0.0294.) The PASP levels of patients found in the mean PASP values between the KTS and ve- with KTS or extensive venous malformations did not cor- nous malformation groups (42.50 [8.67] mm Hg in pa- relate with the levels of D-dimer, vWF, and fibrinogen. tients with KTS vs 41.71 [8.54] in patients with venous malformations; P=.80). There were 2 patients diagnosed as having KTS with COMMENT hemicorporal affectation and another with involvement of both lower extremities. When we compared the PASP This study shows statistically significant differences in values of these 3 patients with those of the rest of the pa- the values of PASP in patients with extensive venous mal- tients, we observed statistically significant differences (the formations and also in patients with KTS compared with mean [SD] PASP values in patients with very extensive the respective healthy control populations. It has previ- malformations were 52.67 [8.08] vs 41.07 [7.87] in the ously been suggested that recurrent or unresolved pul- rest of the patients; P=.02). monary embolisms from the vascular malformation due All children younger than 15 years with KTS (n=4) to hypercoagulability can lead to the development of and 4 of the 5 children with venous malformations had CTEPH in patients with KTS and pure extensive venous borderline or pathologic PASP. D-dimer level was deter- malformations.10,11 CTEPH results from incomplete reso- mined in 24 of the patients and in 29 of the healthy con- lution of the vascular obstruction caused by pulmonary trols, levels of fibrinogen in 27 of the patients and in 29 embolism. Pulmonary hemodynamic progression is of the healthy controls, and levels of vWF in 27 of the thought to be the consequence of the development of a patients and in 29 of the healthy controls. There was a secondary arteriopathy in nonobstructed precapillary pul- marked difference of D-dimer levels between groups; monary vessels. Pulmonary small vascular malforma- PϽ.001) (Table 1). When subgroups according to PASP tions are thought to play an important role in other pul- levels were analyzed, the mean D-dimer value in the group monary vascular disorders such as veno-occlusive disease with normal PASP levels was 287.92 (641.92) ng/mL and pulmonary capillary hemangiomatosis. It was not con- (n=39; 30 controls and 9 cases); in the borderline group, firmed in these patients if the cause of the high values of 985.04 (1660.58) ng/mL (n=18; 2 controls and 16 cases); PASP observed was due to CTEPH. and in the group with pathological PASP level, 978.98 Coagulation disorders (LIC) have been reported in pa- (614.99) ng/mL (n=7, all cases) (Figure 4). There were tients with venous malformations of the limbs and differences between the group with normal PASP levels trunk,4,5,20 mainly with elevations in D-dimer levels. D- and the group with pathological PASP levels (P=.001) dimer, a split product of fibrin degradation by plasmin, and also between the group with normal PASP levels and has been used as a marker for various diseases.21,22 LIC the group with borderline PASP levels (P=.005). Over- is frequently associated with venous malformations, and

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Patients With

VM KTS P Variable (n=14) (n=18) Value Sex .48 Male 6 11 Female 8 7 Age, mean (SD), y 21.6 (12.3) 30.4 (15.1) .09 Location, No. of malformations NA Lower extremity 6a 15b Upper extremity 2 Trunk 1 Head and neck 1 Hemicorporal 2 2 Multiples sites 2 1 PASP level, mean (SD), mm Hg 41.71 (8.54) 42.50 (8.67) .80 Fibrinogen level, mean (SD), mg/dL 228.55 (57.18) 283.0 (94.58) .08 vWF, mean No. (%) 112.0 (45.93) 132.94 (56.05) .27 D-dimer level, mean (SD), ng/mL 2316.16 (1724.80) 391.40 (399.74) Ͻ.001

Abbreviations: KTS, Klippel-Tre´naunay syndrome; NA, not applicable; PASP, pulmonary artery systolic pressure; VM, venous malformation; vWF, von Willebrand factor. SI conversion factor: To convert fibrinogen to micromoles per liter, multiply by 0.0294. a In 1 patient, the VM affected both legs. b The malformation in 2 patients with KTS affected both legs.

6000 ∗

4000 50

∗ 40 2000 D-dimer Level, ng/mL

30 ∗ PASP Level, mm Hg PASP 0

20 Normal Borderline Pathological PASP Level

10 Figure 4. D-dimer levels according the value of pulmonary artery systolic Controls Patients pressure (PASP). The bottom and top of the boxes are the 25th and 75th percentiles (the lower and upper quartiles, respectively), and the bands near Figure 3. Pulmonary artery systolic pressure in healthy controls and the middle of the box are the 50th percentile (median). The asterisks indicate patients. The bottom and top of the boxes are the 25th and 75th percentiles outliers. (the lower and upper quartiles, respectively), and the bands near the middle of the boxes are the 50th percentile (median). has not been previously described in patients with vas- large surface area and muscle involvement are strong pre- cular malformations. Von Willebrand factor is a large mul- dictable criteria for higher levels of D-dimers.6 This could timeric glycoprotein present in blood plasma and is pro- explain why the patients included in this study with large duced constitutively in the endothelium. It is a marker and deep venous malformations have higher levels of D- of endothelium dysfunction. In pathological condi- dimers than patients with KTS. It has been reported that tions, endothelial cell stimulation is followed by rapid in patients with idiopathic PAH, mean D-dimer levels were release of vWF from Weibel-Palade bodies and plasma significantly higher than in the matched control group.23 vWF levels increase.26,27 If endothelial cell function is re- There is also evidence to suggest that D-dimer levels in stored, vWF: Ag levels return to normal. Von Wille- patients with idiopathic PAH are associated with dis- brand factor independently predicts long-term survival ease severity and prognosis.24 Elevated levels of D- in patients with PAH.28 Also, in secondary pulmonary hy- dimer have also been found in secondary PAH.25 To our pertension, it has been demonstrated that levels of vWF knowledge, we show for the first time that levels of D- are higher in patients than in controls.25 Although the dimer in plasma are highly correlated with PASP values common pathogenic mechanisms of PAH are not known, in patients with slow-flow vascular malformations. pulmonary vascular changes of distinctive causes lead to This study also detected a moderately positive corre- endothelial dysfunction and activation of a cascade of dif- lation between PASP and vWF, which to our knowledge ferent regulatory systems (coagulatory, inflammatory, and

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 PAH is a serious process that leads to right ventricu- Patients with extensive slow-flow lar insufficiency and can cause death. Most patients are vascular malformations diagnosed in advanced phases when they already have symptoms. Based on these results, an echocardiogram Echocardiogram should be performed in all patients diagnosed as having an extensive slow-flow vascular malformation, although such a measure may not be necessary in those ≥ PASP < 50 mm Hg PASP 50 mm Hg with medium or small malformations (Figure 5). Al- tered PASP values may exist in children with extensive Cardiologists or pneumonologist slow-flow vascular malformations; therefore, there is no evaluation justification for waiting until the patient is an adult to perform an echocardiogram. Furthermore, the echocar- Symptoms? diogram is a painless and innocuous test and can be eas- ily performed in children. More extensive studies are needed to confirm the high prevalence of PAH in asymp- Yes No tomatic patients with slow-flow vascular malformations and to determine who should be referred for a baseline RSH cardiac study to exclude the presence of PAH.

Accepted for Publication: May 6, 2010. Normal mPAP < 25 mm Hg mPAP > 25 mm Hg Closely Correspondence: Pedro Redondo, MD, PhD, Depart- monitoring monitoring (echocardiogram (echocardiogram ment of Dermatology, University Clinic of Navarra, 31008 every 2-3 y) every 8-12 mo) Pamplona, Spain ([email protected]). Author Contributions: All authors had full access to all Closely monitoring Unit specialized of the data in the study and take responsibility for the (echocardiogram in pulmonary every 8-12 mo) hypertension integrity of the data and the accuracy of the data analysis. Drs Rodrı´guez-Man˜ ero and Aguado contributed equally to this work and both should be considered first Figure 5. Management schema of patients with extensive slow-flow vascular malformations. If the pulmonary artery systolic pressure (PASP) is less than authors. Study concept and design: Rodrı´guez-Man˜ ero, 50 mm Hg, no other decisions must be taken and patients should be Aguado, and Redondo. Acquisition of data: Rodrı´guez- reevaluated by echocardiogram every 2 to 3 years. If the PASP level is equal to Man˜ ero, Aguado, and Redondo. Analysis and interpreta- or higher than 50 mm Hg, an assessment should be made by a cardiologist or tion of data: Rodrı´guez-Man˜ ero and Aguado. Drafting of pneumonologist. In the case of asymptomatic patients, close monitoring (an echocardiogram every 8-12 months) may prove sufficient. If patients complain the manuscript: Rodrı´guez-Man˜ ero, Aguado, and Re- of symptoms such as dyspnea, asthenia, or edema, they should undergo dondo. Critical revision of the manuscript for important in- catheterization of the right side of the heart (RSH) to confirm the diagnosis. tellectual content: Rodrı´guez-Man˜ ero, Aguado, and Re- Those patients whose mean pulmonary artery pressure (mPAP) (as measured by catheterization of the RSH) is more than 25 mm Hg must be referred to a dondo. Statistical analysis: Rodrı´guez-Man˜ ero, Aguado, unit specializing in pulmonary hypertension. and Redondo. Financial Disclosure: None reported. Additional Contributions: Alejandro Sierra, MD, PhD, and proliferative), resulting in an imbalance in vasoconstric- Antonio Martinez de la Cuesta, MD, provided invaluable tion and smooth muscle cell proliferation, the main cul- help in the evaluation and treatment of the patients, and prit of pulmonary hypertension.29 Juan Jose Gavira, MD, and Pedro Azca´rate, MD, PhD, pro- Although, traditionally, pulmonary thromboembo- vided assistance with the echographic studies. lism has been considered only in patients with KTS, isolated cases of pulmonary arterial hypertension due to REFERENCES chronic thromboembolism in patients with pure ve- 10 nous malformations have previously been reported. To 1. Mulliken JB. Vascular malformations of the head and neck. In: Mulliken JB, Young date, venous malformations have not been considered to AE, eds. Vascular Birthmarks: Hemangiomas and Vascular Malformations. Phila- be a risk for pulmonary embolism because they are more delphia, PA: WB Saunders; 1988. separated from the venous circulation than KTS. How- 2. Jacob AG, Driscoll DJ, Shaughnessy WJ, Stanson AW, Clay RP, Gloviczki P. Klippel-Tre´naunay syndrome: spectrum and management. Mayo Clin Proc. 1998; ever, “varicose-like” forms of venous malformations may 73(1):28-36. have a closer relationship with the venous system. All pa- 3. Mazoyer E, Enjolras O, Bisdorff A, Perdu J, Wassef M, Drouet L. Coagulation dis- tients included in the study had KTS or extensive slow- orders in patients with venous malformation of the limbs and trunk: a case se- flow vascular malformations. Patients with small or in- ries of 118 patients. Arch Dermatol. 2008;144(7):861-867. termediate malformations were not included. Severe LIC 4. Enjolras O, Ciabrini D, Mazoyer E, Laurian C, Herbreteau D. Extensive pure venous malformations in the upper or lower limb: a review of 27 cases. J Am Acad is associated with large lesions that often affect an ex- Dermatol. 1997;36(2, pt 1):219-225. tremity. Just as there is an association between the size 5. Mazoyer E, Enjolras O, Laurian C, Houdart E, Drouet L. Coagulation abnormalities and the extent of a venous malformation and D-dimer associated with extensive venous malformations of the limbs: differentiation from levels,6 a similar connection could exist regarding the po- Kasabach-Merritt syndrome. Clin Lab Haematol. 2002;24(4):243-251. 6. Dompmartin A, Acher A, Thibon P, et al. Association of localized intravascular tential risk of PAH in patients with venous malforma- coagulopathy with venous malformations. Arch Dermatol. 2008;144(7):873- tions, in that the larger the malformations, the greater 877. the risk. 7. Dompmartin A, Ballieux F, Thibon P, et al. Elevated D-dimer level in the differ-

(REPRINTED) ARCH DERMATOL/ VOL 146 (NO. 12), DEC 2010 WWW.ARCHDERMATOL.COM 1351

©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 ential diagnosis of venous malformations. Arch Dermatol. 2009;145(11):1239- tation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary 1244. hypertension. Eur Respir J. 2009;34(6):1219-1263. 8. Samuel M, Spitz L. Klippel-Trenaunay syndrome: clinical features, complica- 19. Romań JS, Hernańdez FJ, Palma MJ, Medina CO. Diagnosis and treatment of tions and management in children. Br J Surg. 1995;82(6):757-761. pulmonary hypertension [in Spanish]. Rev Clin Esp. 2008;208(3):142-155. 9. Baskerville PA, Ackroyd JS, Lea Thomas M, Browse NL. The Klippel-Trenaunay 20. Redondo P. The hidden face of venous malformations: a multidisciplinary thera- syndrome: clinical, radiological and haemodynamic features and management. peutic approach. Arch Dermatol. 2008;144:922-926. Br J Surg. 1985;72(3):232-236. 21. Rowbotham BJ, Carroll P, Whitaker AN, et al. Measurement of crosslinked fibrin 10. Oduber CE, Gerdes VE, van der Horst CM, Bresser P. Vascular malformations as un- derivatives: use in the diagnosis of venous thrombosis. Thromb Haemost. 1987; derlying cause of chronic thromboembolism and pulmonary hypertension. J Plast 57(1):59-61. Reconstr Aesthet Surg. 2009;62(5):684-689. 22. Bounameaux H, de Moerloose P, Perrier A, Reber G. Plasma measurement of 11. Muluk SC, Ginns LC, Semigran MJ, Kaufman JA, Gertler JP. Klippel-Treńaunay D-dimer as diagnostic aid in suspected venous thromboembolism: an overview. syndrome with multiple pulmonary emboli: an unusual cause of progressive pul- Thromb Haemost. 1994;71(1):1-6. monary dysfunction. J Vasc Surg. 1995;21(4):686-690. 23. Shitrit D, Bendayan D, Rudensky B, et al. Elevation of ELISA D-dimer levels in 12. Walder B, Kapelanski DP, Auger WR, Fedullo PF. Successful pulmonary throm- patients with primary pulmonary hypertension. Respiration. 2002;69(4):327- boendarterectomy in a patient with Klippel-Trenaunay syndrome. Chest. 2000; 329. 117(5):1520-1522. 24. Shitrit D, Bendayan D, Bar-Gil-Shitrit A, et al. Significance of a plasma D-dimer 13. Burbelko M, Kalinowski M, Wagner HJ. Rare cause of chronic recurrent pulmo- test in patients with primary pulmonary hypertension. Chest. 2002;122(5): nary emboli and pulmonary artery hypertension [in German]. Dtsch Med 1674-1678. Wochenschr. 2006;131(15):811-814. 25. Lopes AA, Caramuru´ LH, Maeda NY. Endothelial dysfunction associated with chronic 14. Ulrich S, Fischler M, Walder B, Pfammatter T, Speich R. Klippel-Trenaunay syndrome with small vessel pulmonary arterial hypertension. Thorax. 2005;60 intravascular coagulation in secondary pulmonary hypertension. Clin Appl Thromb (11):971-973. Hemost. 2002;8(4):353-358. 15. Gianlupi A, Harper RW, Dwyre DM, Marelich GP. Recurrent pulmonary embo- 26. Booth F, Allington MJ, Cederholm-Williams SA. An in vitro model for the study lism associated with Klippel-Trenaunay-Weber syndrome. Chest. 1999;115 of acute release of von Willebrand factor from human endothelial cells. Br J (4):1199-1201. Haematol. 1987;67(1):71-78. 16. Hein KD, Mulliken JB, Kozakewich HPW, Upton J, Burrows PE. Venous malfor- 27. Paleolog EM, Crossman DC, McVey JH, Pearson JD. Differential regulation by mations of skeletal muscle. Plast Reconstr Surg. 2002;110(7):1625-1635. cytokines of constitutive and stimulated secretion of von Willebrand factor from 17. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of endothelial cells. Blood. 1990;75(3):688-695. pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12)(suppl S): 28. Kawut SM, Horn EM, Berekashvili KK, Widlitz AC, Rosenzweig EB, Barst RJ. 40S-47S. von Willebrand factor independently predicts long-term survival in patients with 18. Galiè N, Hoeper MM, Humbert M, et al; Task Force for Diagnosis and Treatment pulmonary arterial hypertension. Chest. 2005;128(4):2355-2362. of Pulmonary Hypertension of European Society of Cardiology (ESC); European 29. Eddahibi S, Morrell N, d’Ortho MP, Naeije R, Adnot S. Pathobiology of pulmo- Respiratory Society (ERS); International Society of Heart and Lung Transplan- nary arterial hypertension. Eur Respir J. 2002;20(6):1559-1572.

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We wish to thank all of the reviewers who have gener- ously and thoughtfully assisted the Editorial Board, our authors, and our readers during the past year. A full list of our reviewers from 2010 is available at http://www .archdermatol.com. June K. Robinson, MD Editor Jeffrey P. Callen, MD Associate Editor

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