Vasculitis and Thrombophlebitis Workup
- Author: Nadia Jennifer Chiara Luca, MD; Chief Editor: Lawrence K Jung, MD more...
Investigations must be performed to detect signs of inflammation, to determine the type and extent of organ involvement, to test for vasculitis-specific autoantibodies, and to rule out secondary causes. Note that the degree of inflammation often differs between diseases and among individual patients.
General laboratory tests
CBC count and differential may reveal normochromic, normocytic anemia; leukocytosis; thrombocytosis consistent with inflammatory process; and eosinophilia in Churg-Strauss syndrome.
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be elevated, but these findings are not sensitive or specific.
C3 and C4 levels are usually elevated, except in hypocomplementemic urticarial vasculitis.
Albumin levels may be low due to chronic inflammation, third spacing, or vascular leakage.
von Willebrand factor antigen (factor VIII-related antigen) may be elevated.
BUN, creatinine, liver enzyme levels may be abnormal, depending on involvement.
Urine studies for hematuria and/or proteinuria are indicated.
Lumbar puncture may reveal pleocytosis, elevated protein levels, and/or elevated opening pressure in childhood primary angiitis of the CNS (PACNS)
The initial test for antineutrophil cytoplasmic antibody (ANCA) is indirect immunofluorescence to detect staining pattern, either cytoplasmic or perinuclear.
If positive results are noted, test for reactivity to proteinase 3 (PR3) and myeloperoxidase (MPO) by enzyme-linked immunoassay (ELISA)
ANCA positivity is noted in approximately 90% of pediatric patients with granulomatosis with polyangiitis (GPA) (formerly Wegener granulomatosis), 79% of who are cytoplasmic.
PR3-ANCA and MPO-ANCA positivity have a high sensitivity and specificity for the diagnosis of GPA and microscopic polyangiitis (MPA), respectively.
The association of Churg-Strauss syndrome and ANCA positivity is approximately 40%.
Note that an atypical ANCA finding is nonspecific and may be seen in other inflammatory conditions such as infection and inflammatory bowel disease.
Anti-glomerular basement membrane (GBM) antibody testing is indicated for pulmonary renal syndromes.
Other autoantibodies such as anti-nuclear antibody (ANA) and rheumatoid factor (RF) are rarely positive
Infectious work-up (as indicated)
See the list below:
Bacterial - Mycoplasma PCR and serology, antistreptolysin O test (ASOT), syphilis serology, Mantoux skin test
Viral - Serology for hepatitis B and C, parvovirus B19, HIV, herpes simplex virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella
Antiphospholipid antibody syndrome studies include the following:
Prolonged activated partial thromboplastin time (aPTT), which does not correct with mixing
Screening for lupus anticoagulant
Anticardiolipin antibody by ELISA
Anti-β2-microglobulin-1 antibody by ELISA
Classification criteria for pediatric antiphospholipid antibody syndrome includes the following clinical criteria for vascular thrombosis: One or more clinical episodes of arterial, venous, or small-vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (ie, unequivocal findings of appropriate imaging studies or histopathology). For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.
The laboratory criteria include the following:
Anticardiolipin antibody of immunoglobulin G (IgG) and/or immunoglobulin M (IgM) isotype in serum or plasma - Must be present in medium or high titre (ie, >40 GPL or MPL, or >99th percentile) on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA
Anti-β 2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma - Must be present in titre >99th percentile, on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA
Lupus anticoagulant in plasma - Must be present on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis
Pediatric antiphospholipid syndrome is considered to be present if the clinical criterion and at least I of the laboratory criteria are met.
Other thrombophilia work-up includes protein C, protein S, antithrombin III, factor V Leiden mutation, homocysteine, prothrombin gene mutation (G20210A), and methylene tetrahydrofolate reductase (MTHFR) mutation.
Imaging is essential for evaluation of blood vessels and of end-organ damage. In particular, vascular imaging is often imperative for diagnosis and follow-up of the disease. Information regarding both luminal blood flow and vessel wall changes is important. Conventional angiography generally provides information about blood flow, clot formation, and collateral blood flow; whereas CT and/or magnetic resonance (MR) angiography provide visualization of vessel wall thickness and fragility, aneurysm formation, and overall disease activity.
This is indicated to screen for pulmonary involvement in granulomatosis with polyangiitis (formerly Wegener granulomatosis), Churg-Strauss syndrome, microscopic polyangiitis, Takayasu arteritis (TA), and Behçet syndrome.
A characteristic of CSS is fluctuating infiltrates (see the image below).
CT scan of the sinuses
Turbinate mucosal thickening with associated sinusitis and possible erosive changes is seen in granulomatosis with polyangiitis (see the image below).
Orbital pseudotumors may be seen in granulomatosis with polyangiitis and microscopic polyangiitis.
CT scan of the chest
In granulomatosis with polyangiitis, nodules (may be cavitary and/or multifocal), ground-glass opacification, air-space opacification, mediastinal lymphadenopathy, and pleural thickening and effusion may be seen.
In Churg-Strauss syndrome, nodules, ground-glass opacification, bronchial wall thickening or dilatation, consolidation, septal thickening, and tree-in-bud pattern may be seen (see the image below).
In microscopic polyangiitis, patchy or confluent bilateral areas of consolidation may be seen, mainly in lower lobes.
Echocardiography is indicated to assess for coronary artery involvement, especially in Kawasaki disease (KD)
Head CT scan or MRI
These studies may reveal acute ischemia or hemorrhage in patients with CNS symptoms
In large or medium-vessel childhood PACNS, T2-hyperintense focal areas of acute ischemia in a vascular distribution is noted. Diffusion weighted imaging (DWI) findings are positive. Vessel wall enhances with gadolinium.
In small-vessel childhood PACNS, T2-fluid-attenuated inversion-recovery (FLAIR) hyperintensities that do not conform to a vascular territory are noted. DWI findings are negative.
CT angiography, MR angiography, or conventional angiography plus MRI vessel wall imaging (gadolinium enhancement)
These studies are used to assess for large and/or medium vessel vasculitis.
Angiography (CT, MR, conventional) of the aorta and its main branches is indicated when investigating for Takayasu arteritis.
Head MR angiography is diagnostic in large/medium vessel childhood PACNS.
Vascular imaging in polyarteritis nodosa (PAN) must be done with conventional angiography because medium-sized vessels are involved (site depends on clinical features); findings include “beading” of vessels caused by alternating areas of vascular narrowing and dilatation.
Consider angiography in Behçet disease (site depends on clinical features).
CT/MR venography is indicated if venous thrombosis is suspected in antiphospholipid antibody syndrome, Behçet disease, and polyarteritis nodosa.
Ultrasonography with Doppler
This is used to identify thromboses in deep venous system, renal vessels, and transcranial vessels.
Positron emission tomography (PET) scan
This can detect subtle evidence of inflammation to identify potential sites of vasculitis.
See the list below:
Pulmonary function tests – Both obstructive and restrictive patterns seen in pulmonary vasculitis
Electrocardiography – To identify signs of myocarditis or pericarditis
Nerve conduction studies – In patients with peripheral nerve involvement
Electroencephalogram – In patients with CNS involvement
Bronchoscopy/lavage – May be required in patients with lung involvement
Tissue biopsy may be necessary to confirm a diagnosis of vasculitis in systemic and cutaneous polyarteritis nodosa (PAN), ANCA vasculitides, childhood PACNS, and infrequently in Henoch-Schönlein purpura.
Henoch-Schönlein purpura - Skin and/or renal biopsy
Polyarteritis nodosa - Skin biopsy
ANCA-vasculitides - Sinus, renal, lung, and/or skin biopsy
Childhood PACNS - Lesional brain biopsy often needed in small-vessel CNS vasculitis
See the list below:
Takayasu arteritis: Inflammatory infiltrate is composed of T cells. Macrophages are arranged into granulomas with giant cells. Concentric thickening of all layers of the artery wall (intima, media and adventitia) is noted.
Polyarteritis nodosa: Acute and segmental necrotizing vasculitis of medium-sized arteries is seen with an inflammatory infiltrate composed of neutrophils and eosinophils within the vessel walls and extravasation of erythrocytes and fibrin.
Churg-Strauss syndrome: In the lung, extravascular microgranulomas filled with eosinophils and intramural eosinophilic infiltrate are noted.
Granulomatosis with polyangiitis (GPA) (formerly Wegener granulomatosis): In the lung, granulomatous inflammation with mononuclear infiltrate including T cells, macrophages/histiocytes, and giant cells are noted.
GPA and microscopic polyangiitis: Renal histologic findings include "pauci-immune" (ie, little immune deposition on immunofluorescence) necrotizing glomerulonephritis with large circumferential crescents, segmental loss of basement membrane, and tubulointerstitial inflammation.
Henoch-Schönlein purpura: Immunofluorescence demonstrates deposition of IgA, C3, and fibrin in the walls of affected blood vessels within the dermis and the endothelial and mesangial cells of the kidney. Skin biopsy reveals features of leukocytoclastic vasculitis with infiltrate of neutrophils and mononuclear cells.
Childhood PACNS: Segmental nongranulomatous intramural infiltration of predominantly T lymphocytes involves small arteries, arterioles, capillaries, and/or venules. Surrounding reactive changes may include gliosis, calcification, and pallor of myelin staining.
Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994 Feb. 37(2):187-92. [Medline].
Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med. 1997 Nov 20. 337(21):1512-23. [Medline].
Ozen S, Anton J, Arisoy N, et al. Juvenile polyarteritis: results of a multicenter survey of 110 children. J Pediatr. 2004 Oct. 145(4):517-22. [Medline].
Akikusa JD, Schneider R, Harvey EA, et al. Clinical features and outcome of pediatric Wegener's granulomatosis. Arthritis Rheum. 2007 Jun 15. 57(5):837-44. [Medline].
Peco-Antic A, Bonaci-Nikolic B, Basta-Jovanovic G, et al. Childhood microscopic polyangiitis associated with MPO-ANCA. Pediatr Nephrol. 2006 Jan. 21(1):46-53. [Medline].
Boyer D, Vargas SO, Slattery D, Rivera-Sanchez YM, Colin AA. Churg-Strauss syndrome in children: a clinical and pathologic review. Pediatrics. 2006 Sep. 118(3):e914-20. [Medline].
Sarica-Kucukoglu R, Akdag-Kose A, KayabalI M, et al. Vascular involvement in Behçet's disease: a retrospective analysis of 2319 cases. Int J Dermatol. 2006 Aug. 45(8):919-21. [Medline].
Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J Med. 2003 Jul 10. 349(2):160-9. [Medline].
Dedeoglu F, Sundel RP. Vasculitis in children. Rheum Dis Clin North Am. 2007 Aug. 33(3):555-83. [Medline].
Jennette JC, Falk RJ. New insight into the pathogenesis of vasculitis associated with antineutrophil cytoplasmic autoantibodies. Curr Opin Rheumatol. 2008 Jan. 20(1):55-60. [Medline].
Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest. 2002 Oct. 110(7):955-63. [Medline]. [Full Text].
Md Yusof MY, Vital EM, Das S, Dass S, Arumugakani G, Savic S, et al. Repeat cycles of rituximab on clinical relapse in ANCA-associated vasculitis: identifying B cell biomarkers for relapse to guide retreatment decisions. Ann Rheum Dis. 2015 Apr 8. [Medline].
Janeczko LL. Naive B-Lymphopenia Possible Biomarker of Disease Activity in Vasculitis. http://www.medscape.com/viewarticle/843633. Available at http://www.medscape.com/viewarticle/843633. April 24, 2015; Accessed: July 1, 2015.
Lau KK, Wyatt RJ, Moldoveanu Z, et al. Serum levels of galactose-deficient IgA in children with IgA nephropathy and Henoch-Schönlein purpura. Pediatr Nephrol. 2007 Dec. 22(12):2067-72. [Medline].
Gardner-Medwin JM, Dolezalova P, Cummins C, Southwood TR. Incidence of Henoch-Schönlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet. 2002 Oct 19. 360(9341):1197-202. [Medline].
Wu M-H, Nakamura Y, Burns JC, et al. State-of-the-art basic and clinical science of Kawasaki disease. Pediatric Health. 2008. 2:405-409.
Cabral DA, Uribe AG, Benseler S, et al. Classification, presentation, and initial treatment of Wegener's granulomatosis in childhood. Arthritis Rheum. 2009 Nov. 60(11):3413-24. [Medline].
Phillip R, Luqmani R. Mortality in systemic vasculitis: a systematic review. Clin Exp Rheumatol. 2008 Sep-Oct. 26(5 Suppl 51):S94-104. [Medline].
Narchi H. Risk of long term renal impairment and duration of follow up recommended for Henoch-Schonlein purpura with normal or minimal urinary findings: a systematic review. Arch Dis Child. 2005 Sep. 90(9):916-20. [Medline]. [Full Text].
Elbers J, Benseler SM. Central nervous system vasculitis in children. Curr Opin Rheumatol. 2008 Jan. 20(1):47-54. [Medline].
Reiff A. Ocular complications of childhood rheumatic diseases: nonuveitic inflammatory eye diseases. Curr Rheumatol Rep. 2009 Jul. 11(3):226-32. [Medline].
Avcin T, Cimaz R, Rozman B. The Ped-APS Registry: the antiphospholipid syndrome in childhood. Lupus. 2009 Sep. 18(10):894-9. [Medline].
Levine D, Akikusa J, Manson D, Silverman E, Schneider R. Chest CT findings in pediatric Wegener's granulomatosis. Pediatr Radiol. 2007 Jan. 37(1):57-62. [Medline].
Kim YK, Lee KS, Chung MP, et al. Pulmonary involvement in Churg-Strauss syndrome: an analysis of CT, clinical, and pathologic findings. Eur Radiol. 2007 Dec. 17(12):3157-65. [Medline].
Lauque D, Cadranel J, Lazor R, et al. Microscopic polyangiitis with alveolar hemorrhage. A study of 29 cases and review of the literature. Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P). Medicine (Baltimore). 2000 Jul. 79(4):222-33. [Medline].
Durongpisitkul K, Gururaj VJ, Park JM, Martin CF. The prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the efficacy of aspirin and immunoglobulin treatment. Pediatrics. 1995 Dec. 96(6):1057-61. [Medline].
Weiss PF, Feinstein JA, Luan X, Burnham JM, Feudtner C. Effects of corticosteroid on Henoch-Schönlein purpura: a systematic review. Pediatrics. 2007 Nov. 120(5):1079-87. [Medline].
Chartapisak W, Opastirakul S, Hodson EM, Willis NS, Craig JC. Interventions for preventing and treating kidney disease in Henoch-Schönlein Purpura (HSP). Cochrane Database Syst Rev. 2009 Jul 8. CD005128. [Medline].
Levy-Clarke G, Jabs DA, Read RW, Rosenbaum JT, Vitale A, Van Gelder RN. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology. 2014 Mar. 121(3):785-96.e3. [Medline].
Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis. 2009 Mar. 68(3):310-7. [Medline].
[Guideline] Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2009 Mar. 68(3):318-23. [Medline].
Guerry MJ, Brogan P, Bruce IN, D'Cruz DP, Harper L, Luqmani R. Recommendations for the use of rituximab in anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford). 2012 Apr. 51(4):634-43. [Medline].
Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15. 363(3):221-32. [Medline].
Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010 Jul 15. 363(3):211-20. [Medline].
Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013 Aug 1. 369(5):417-27. [Medline].
Holle JU, Dubrau C, Herlyn K, Heller M, Ambrosch P, Noelle B. Rituximab for refractory granulomatosis with polyangiitis (Wegener's granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations. Ann Rheum Dis. 2012 Mar. 71(3):327-33. [Medline].
Faurschou M, Westman K, Rasmussen N, de Groot K, Flossmann O, Höglund P, et al. Long-term outcome of a clinical trial comparing methotrexate to cyclophosphamide for remission induction of early systemic ANCA-associated vasculitis. Arthritis Rheum. 2012 May 21. [Medline].
Roubaud-Baudron C, Pagnoux C, Méaux-Ruault N, Grasland A, Zoulim A, LE Guen J. Rituximab maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis. J Rheumatol. 2012 Jan. 39(1):125-30. [Medline].
Filocamo G, Buoncompagni A, Viola S, Loy A, Malattia C, Ravelli A, et al. Treatment of Takayasu's arteritis with tumor necrosis factor antagonists. J Pediatr. 2008 Sep. 153(3):432-4. [Medline].
Ruiz-Irastorza G, Hunt BJ, Khamashta MA. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum. 2007 Dec 15. 57(8):1487-95. [Medline].
Lee BB, Laredo J, Neville R, Villavicencio JL. Endovascular management of takayasu arteritis: is it a durable option?. Vascular. 2009 May-Jun. 17(3):138-46. [Medline].
Roediger FC, Orloff LA, Courey MS. Adult subglottic stenosis: management with laser incisions and mitomycin-C. Laryngoscope. 2008 Sep. 118(9):1542-6. [Medline].
McCrindle BW. Kawasaki disease: a childhood disease with important consequences into adulthood. Circulation. 2009 Jul 7. 120(1):6-8. [Medline].
Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004 Oct 26. 110(17):2747-71. [Medline].
Holve TJ, Patel A, Chau Q, Marks AR, Meadows A, Zaroff JG. Long-term cardiovascular outcomes in survivors of Kawasaki disease. Pediatrics. 2014 Feb. 133(2):e305-11. [Medline].
Benseler SM, deVeber G, Hawkins C, et al. Angiography-negative primary central nervous system vasculitis in children: a newly recognized inflammatory central nervous system disease. Arthritis Rheum. 2005 Jul. 52(7):2159-67. [Medline].
Cantez S, Benseler SM. Childhood CNS vasculitis: a treatable cause of new neurological deficit in children. Nat Clin Pract Rheumatol. 2008 Sep. 4(9):460-1. [Medline].
Jennette JC, Xiao H, Falk RJ. Pathogenesis of vascular inflammation by anti-neutrophil cytoplasmic antibodies. J Am Soc Nephrol. 2006 May. 17(5):1235-42. [Medline].
McCrindle BW, McIntyre S, Kim C, Lin T, Adeli K. Are patients after Kawasaki disease at increased risk for accelerated atherosclerosis?. J Pediatr. 2007 Sep. 151(3):244-8, 248.e1. [Medline].
|Localized||Upper and/or lower respiratory tract disease without any other systemic
involvement or constitutional symptoms
|Any, without organ-threatening or life-threatening disease|
|Generalized||Renal or other organ-threatening disease, serum creatinine >500
μmol/L (5.6 mg/dL)
|Severe||Renal or other vital organ failure, serum creatinine >500 μmol/L (5.6 mg/dL)|
|Refractory||Progressive disease unresponsive to glucocorticoids and cyclophosphamide|