Primary Raynaud's phenomenon in an infant: a case report and review of literature
© Sharathkumar and Castillo-Caro; licensee BioMed Central Ltd. 2011
Received: 3 November 2010
Accepted: 18 July 2011
Published: 18 July 2011
Raynaud's phenomenon (RP) is an extremely unusual finding in early infancy. In the present report we describe a one-month-old previously healthy male infant who presented with unilateral acrocyanosis. Although infantile acrocyanosis is known to be a benign and self-resolving condition, it is generally bilateral and symmetric. The unilateral nature of the acrocyanosis was an atypical finding in this infant. Consequently, he was closely monitored to evaluate the progression of his acrocyanosis. Based on his benign clinical course and failure to demonstrate other etiologies contributing to his acrocyanosis, he was diagnosed to have primary RP. Due to the rarity of RP in children, we review the progress in understanding the pathophysiology, epidemiology and management of RP and additionally discuss the differential diagnosis of unilateral and bilateral acrocyanosis in infants.
Raynaud's phenomenon (RP) was first described by Maurice Raynaud in 1862 . Classically, the initial description of RP involved triphasic color changes in the digits, with blanching (white) leading to cyanosis (blue) followed by reactive hyperemia (red) [2, 3]. However, it has been realized that not every patient experiences all 3 phases of color change and the majority of patients present with uniphasic color change involving an isolated bluish discoloration of digits commonly known as acrocyanosis [4–6]. Unlike RP, acrocyanosis is a common phenomenon in infants and young children [4–7]. Acrocyanosis is generally bilateral, symmetric and involves hands and feet. Since infantile acrocyanosis is a benign and self-resolving condition, it does not require medical attention [7, 8]. Rarely, acrocyanosis in infants can be caused by RP and may require immediate medical attention to prevent complications of RP [9–13]. In this report, we describe an infant who initially presented with unilateral acrocyanosis and was diagnosed to have primary RP based on his subsequent clinical course. In view of the rarity of RP in infants and young children, the literature about RP is reviewed with a specific focus on the pediatric population. To help differentiate benign acrocyanosis from acrocyanosis associated with other serious conditions, the differential diagnosis of unilateral and bilateral acrocyanosis in infants is also discussed.
A one-month-old healthy male infant was brought to his pediatrician's office for the evaluation of bluish to blackish discoloration of his left hand. His mother incidentally noted this color change while she was changing his diaper. She did not recall any trauma or insect bite. She denied using naphthalene balls in the storage area for the infant's clothes. This history was helpful to exclude methemoglobinemia as exposure to naphthalene balls can cause infantile acrocyanosis ). He was breast-fed and his mother was the primary care taker. The infant's birth history was unremarkable except for neonatal physiological jaundice treated with phototherapy for 5 days. His past history was noteworthy only for a history of constipation. His family history was significant for ischemic heart disease at a young age (< 55 years old) in multiple members of his father's family. His father died at the age of 42 years due to a massive myocardial infarction. His mother had a history of migraines. He had three healthy siblings (three brothers, ages 11, 10 and 8 years).
Upon arrival at the outside hospital, he was an alert and healthy infant in no acute distress. His physical examination was normal including vital signs, growth and development except for acrocyanosis of his left hand with a clear demarcation at the wrist. His left palm was cooler than the rest of the extremities with sluggish capillary refill (~3 seconds). The peripheral and central pulses were equal and regular bilaterally. He was able to move all the extremities without any pain. The elevated arm stress test was negative for worsening of cyanosis or weakening of the radial pulse, thereby lessening the possibility of thoracic outlet syndrome. He was referred to a tertiary pediatric facility where he was admitted for further evaluation.
Evaluation during hospitalization
Upper extremity duplex ultrasound, MRI/MRA/MRV of head, neck and left upper extremity were performed to rule out anatomical disturbances in vascular supply. Each test was negative. These results excluded several conditions, including thromboembolism, thoracic outlet syndrome contributing to compression of subclavian vein, vascular anomalies, and the presence of a mass or tumors in the region of cervical plexus including the stellate ganglion. A transthoracic echocardiogram confirmed normal cardiac anatomy and did not demonstrate any intracardiac mass, thrombus, or vegetation to suggest an embolic source for a presumed thrombotic event.
He underwent blood tests to detect infection and other systemic causes of acrocyanosis such as methemoglobinemia, polycythemia, antiphospholipid antibodies, and other hypercoagulable conditions. The complete blood count and comprehensive metabolic panel were normal. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) tests were also normal. His newborn screen for inborn errors of metabolism and hemoglobinopathies was negative. His coagulation tests (PT and aPTT) were normal and antiphospholipid antibodies and antinuclear antibody (ANA) assays were negative. He also underwent testing for inherited thrombophilia such as factor V Leiden mutation, prothrombin gene mutation, and methylene tetrahydrofolate reductase (MTHFR) mutation. Results were positive for homozygosity for a MTHFR C677T mutation with normal homocysteine levels.
Due to the concerns about the transplacental transfer of maternal antibodies contributing to development of RP in this young infant, it was decided to evaluate his mother for other medical conditions associated with RP [14–16]. Her blood work up revealed no evidence for systemic lupus erythematosus (antiphospholipid antibodies, ANA, antidsDNA), scleroderma (antitopoisomerase 1 antibodies) or cryoglobulinemia (cryoglobulin levels).
Course during hospitalization and outpatient follow up
At admission, he was begun on low molecular weight heparin (LMWH, dose: 1 mg/kg/dose, q 12 hourly) due to the concerns of a thromboembolic event. He showed gradual improvement in discoloration of his hands over next 72-hours. Since there was no evidence of thromboembolism, his LMWH treatment was discontinued after three days and it was decided to follow him closely in an outpatient clinic without any further medical intervention. Over the next few months he continued to have 1-2 self-resolving episodes of acrocyanosis per month, involving both hands along with bluishness of tip of the nose, lips, ears and periumbilical area and each lasting for a few minutes to an hour. They were not associated with cold exposure but were felt to be precipitated by abdominal colic due to constipation. At 9 months of age his initial tests for SLE, and other rheumatic diseases was repeated. This evaluation was normal.
Based on his clinical course, he was diagnosed to have "primary Raynaud's phenomenon". His treatment included laxatives for constipation and close clinical monitoring. Over the next one year, he continued to have occasional episodes of acrocyanosis without any medical consequences. At his last follow up (age 2 years), his growth and development was normal (length and weight at 90th percentile).
Causes of acrocyanosis
Type of acrocyanosis
Local trauma/digital injury
Local infection: Paronechia
Thoracic outlet syndrome
Carpel Tunnel syndrome
Cervical tumors compressing neurovascular bundle*
e.g. Neuroblastoma, stellate ganglion tumor
Thromboembolism of arteries of palmar arch
Reflex Sympathetic dystrophy
Benign acrocyanosis of infancy
Reflex sympathetic dystrophy
Congenital cyanotic heart disease**
Over the last decade significant advances have been made in understanding the pathophysiology of RP [17–21]. Irrespective of the underlying etiology, RP is manifested via vasospasm of the small muscular arteries and arterioles of the digits . Similar to benign acrocyanosis of infancy, RP is also triggered by exposure to cold and emotional stress. It can be asymmetric and may last longer than benign acrocyanosis. Based on the available data, an over- activity of the sympathetic nervous system along with an imbalance of vasodilator and vasocontrictor substances may be the most likely etiology for RP . In patients with RP, digital cutaneous neurons show a deficient release of a potent vasodilator, the calcitonin-gene related peptide. This primary pathology may be exaggerated by other factors as well, some of which are influenced by cold or emotional triggers. For example, in response to cold, various vasoconstricting substances such as catecholamines, endothelin-1, and 5-hydroxytryptamine are released. These chemical mediators could cause digital artery vasoconstriction and the symptoms of RP. In some cases, this could trigger a cascade of neutrophil and platelet activation, which through the release of inflammatory agents such as endothelin-1 and TNF-alpha, contribute to the endothelial damage seen with more severe RP . There is some suggestion that elevated levels of homocysteine, a sulfur amino acid that is proposed as an independent risk factor for atherosclerosis, may have an association with RP [17, 22, 23]. RP appears to have a strong familial component suggesting a genetic link, though this link is yet to be clarified . It is also unclear if constipation can exaggerate the imbalance of vasodilator and vascontrictor substances.
Causes of Raynaud's phenomenon
Connective tissue/autoimmune disorders
Systemic lupus erythematosus,
Antiphospholipid antibodies (APLA) syndrome
Work involving tools with vibrations
Vinyl chloride exposure in plastic industry
Since RP is extremely rare in children, specifically in infants, the knowledge about its epidemiology, clinical spectrum and the natural evolution is quite limited [9, 11–13, 29, 34]. The first description of RP in children appeared in 1967, almost 100 years after the initial description of RP by Raynaud in 1862 . This report described a series of 6 children (ages, 2.5 to 5 years) with classic RP . Since 1967, there are only a handful of reports of RP in children [9, 11, 29, 34]. In general, female children are more predisposed to development of RP and the onset of RP generally occurs around menarche implying the influence of ovarian hormones in the pathogenesis of this entity [4, 11, 34]. Primary RP is more common in children than secondary RP [11, 34]. Earlier reports in children suggest the association of RP with rheumatic diseases in children [34, 36]. Similar to adult literature, pediatric studies suggest that positive ANA and abnormalities of nailfold capillaries may be associated with secondary RP .
The largest cohort study in children provided more insight into the epidemiology of RP in children and showed that RP is highly heterogeneous in children . Although exposure to cold was the primary trigger in the majority, (~70% of children) ~10% did not have any known trigger. Primary RP followed a bimodal pattern of age of onset affecting young infants and teenage population. Half of these children experienced additional symptoms such as pain, tingling, and numbness. Interestingly, 11% (9/82) of children with primary RP were lmisdiagnosed as "acrocyanosis" and 4 of them were younger than 2 years of age. These 4 children uniformly experienced monophasic or biphasic color change involving the whole hand, foot, or both under the influence of cold or without an apparent cause. There are only two case reports describing the RP in infants [9, 29]. Both these infants presented at 5 months of age with severe disease and required treatment with vasodilators. A patient reported by Sayre initially presented with predominant involvement of right foot . Her symptoms were uniphasic and lasted for 72 hours prior to presentation. At the age of 9 months, she showed involvement of fingers as well. An infant described by Krigel et al. , presented with acrocyanosis of toes for 3 days prior to admission and showed classic RP with triphasic color changes. The infant progressed to the development of digital gangrene. This patient died at the age of 8 months due to vasomotor collapse. Her autopsy studies revealed the diagnosis of PAN thus supporting secondary RP as the underlying cause of her acrocyanosis. Our patient presented at an earlier age with mild symptoms but his cyanosis lasted for almost 48-72 hours, similar to both these cases. As transient APLAs have been described in pregnant women , our initial work up was focused on evaluating him and his mother for these antibodies to rule out transplacental transfer of these antibodies contributing to the clinical presentation.
Our patient was evaluated for genetic risk factors of thrombosis due to the concerns about unilateral thrombosis at his presentation and the family history of young age heart attacks . He was homozygous for MTHFR C677T mutation. MTHFR mutation can be associated with hyperhomocysteinemia  and high homocysteine levels are shown to be associated with decreased vasodilation both in animal models  and in humans . On the same note, patients with RP are shown to have elevated homocysteine levels compared to normal controls . In our case the patient's homocyteine levels were normal, making this a less likely etiology for his RP. However, whether MTHFR mutation in itself plays a direct role in vascular instability is yet to be clarified.
Our patient was also evaluated for systemic causes of central cyanosis such as methemoglobinemia and congenital cyanotic heart disease. Generally this evaluation is not required for children with unilateral acrocyanosis. However, maternal anxiety and inability to provide a long-term prognosis of this infant forced the medical team to perform the extensive evaluation. Although during two-years of follow up, there was no indication of the other disorders which might be causal for the development of RP, it is possible that in future his underlying condition may become clinically evident.
Management of RP is generally supportive and relies upon its accurate diagnosis. The mild forms of primary RP can be controlled by non-pharmacologic approaches such as avoidance of exposure to cold or emotional stress. In moderate to severe cases, vasodilator therapy including calcium channel blockers, either systemic or topical, is required to relieve the vasospasm. Rarely prostacycline infusions , antiplatelet agents [44, 45] and antithrombotic therapies  have been used with variable success.
Surgery is reserved for extreme cases and generally involves digital sympathectomy . In the severe forms of the disorder, intravenous infusion of prostacyclin as well as endothelin-1 receptor antagonists and specific inhibitors of phosphodiesterase-5 are emerging as the treatment of choice [48, 49]. Investigational agents for the treatment of RP include selective alpha-2c adrenergic receptor blockers, inhibitors of protein tyrosine kinase and Rho-kinase, as well as calcitonin gene-related peptide. In patients with secondary RP, treatment of underlying disease is critical to control the episodes of RP.
This case report highlights that despite an improved understanding of the pathophysiology of RP, the diagnosis of primary RP in infants is challenging and It can take weeks to months to confirm the diagnosis. The rarity of its occurrence in infants, the similarities in clinical presentation between primary RP and benign acrocyanosis of infancy, and the absence of diagnostic tests confirming the diagnosis of primary RP contribute to delay in the diagnosing of RP. Clinical clues that should alert the clinician to suspect RP in infancy include the presence of atypical features such as a prolonged acrocyanosis episode (> 72 hours) and/or a unilateral acrocyanosis. A high index of suspicion and close clinical monitoring is required to ensure an accurate diagnosis and appropriate clinical management.
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Conflict of interest
The authors declare that they have no competing interests.
Contributions of Authors
PC and AS conceived the idea and wrote the manuscript. Both authors read and approved the final manuscript.
List of abbreviations
Antineutrophil cytoplasmic antibodies
Erythrocyte sedimentation rate
Low Molecular Weight Heparin
Methylene Tetrahydrofolate reductase
Magnetic Resonance Imaging
Magnetic Resonance Angiogram
Magnetic Resonance Venography
Antineutrophil cytoplasmic antibodies
Activated Partial thromboplastin time
Tumor necrosis factor.
- Raynaud M: On local asphyxia and symmetrical gangrene of the extremities . New researches on the nature and treatment of local asphyxia of the extremities . trans Selected monographs. Edited by: Barlow T. 1988, London: New Sydenham SocietyGoogle Scholar
- Allen EV, Brown GE: Raynaud's disease: a critical review of minimal requisites for diagnosis. Am J Med Sci. 1932, 183: 187-200. 10.1097/00000441-193202000-00004.View ArticleGoogle Scholar
- Summers A: From white to blue to red: Raynaud's phenomenon. Emergency Nurse. 2005, 13: 18-20. 10.1016/j.aaen.2004.10.010.View ArticlePubMedGoogle Scholar
- Block JA, Sequeira W: Raynaud's phenomenon. Lancet. 2001, 357: 2042-2048. 10.1016/S0140-6736(00)05118-7.View ArticlePubMedGoogle Scholar
- Ho M, Belch JJ: Raynaud's phenomenon: state of the art 1998. Scandinavian Journal of Rheumatology. 1998, 27: 319-322. 10.1080/03009749850154311.View ArticlePubMedGoogle Scholar
- Wigley FM: Clinical practice. Raynaud's Phenomenon. New England Journal of Medicine. 2002, 347: 1001-1008. 10.1056/NEJMcp013013.View ArticlePubMedGoogle Scholar
- DiMaio AM, Singh J: The infant with cyanosis in the emergency room. Pediatric Clinics of North America. 2006, 39: 987-1006.Google Scholar
- Charkoudian N: Skin blood flow in adult human thermoregulation: how it works, when it does not, and why. Mayo Clinic Proceedings. 2003, 78: 603-612. 10.4065/78.5.603.View ArticlePubMedGoogle Scholar
- Krieger I, Brough AJ: Raynaud's phenomenon in an infant. Journal of Pediatrics. 1972, 80: 145-151. 10.1016/S0022-3476(72)80474-8.View ArticlePubMedGoogle Scholar
- De Angelis R, Del Medico P, Blasetti P, Cervini C: Raynaud's phenomenon: clinical spectrum of 118 patients. Clinical Rheumatology. 2003, 22: 279-284. 10.1007/s10067-003-0726-1.View ArticlePubMedGoogle Scholar
- Nigrovic PA, Fuhlbrigge RC, Sundel RP: Raynaud's phenomenon in children: a retrospective review of 123 patients. Pediatrics. 2003, 111: 715-721. 10.1542/peds.111.4.715.View ArticlePubMedGoogle Scholar
- Sheldon WB, Lurie DP, Maricq HR, Kahaleh MB, DeLustro FA, Gibofsky A, LeRoy EC: Three siblings with scleroderma (systemic sclerosis) and two with Raynaud's phenomenon from a single kindred. Arthritis & Rheumatism. 1981, 24: 668-676. 10.1002/art.1780240507.View ArticleGoogle Scholar
- Guntheroth WG, Morgan BC, Harbinson JA, Mullins GL: Raynaud's disease in children. Circulation. 1967, 36: 724-729.View ArticlePubMedGoogle Scholar
- Abuaf N, Laperche S, Carsique R, Meyer O, Deschamps A, Rajoely B, Johanet C, Homberg JC: Antimitochondrial antibodies in the antiphospholipid syndrome. Clinical Reviews in Allergy & Immunology. 1995, 13: 57-65. 10.1007/BF02772249.View ArticleGoogle Scholar
- Monti G, Galli M, Invernizzi F, Pioltelli P, Saccardo F, Monteverde A, Pietrogrande M, Renoldi P, Bombardieri S, Bordin G: Cryoglobulinaemias: a multi-centre study of the early clinical and laboratory manifestations of primary and secondary disease. GISC. Italian Group for the Study of Cryoglobulinaemias. Qjm. 1995, 88: 115-126.PubMedGoogle Scholar
- Shero JH, Bordwell B, Rothfield NF, Earnshaw WC: High titers of autoantibodies to topoisomerase I (Scl-70) in sera from scleroderma patients. Science. 4739, 231: 737-740.View ArticleGoogle Scholar
- al-Awami M, Schillinger M, Maca T, Gschwandtner M, Bieglmayer C, Wagner O, Minar E: Homocysteine levels in patients with Raynaud's phenomenon. Vasa. 2002, 31: 87-90. 10.1024/0301-15220.127.116.11.View ArticlePubMedGoogle Scholar
- Cooke JP, Marshall JM: Mechanisms of Raynaud's disease. Vascular Medicine. 2005, 10: 293-307. 10.1191/1358863x05vm639ra.View ArticlePubMedGoogle Scholar
- Herrick AL, Illingworth K, Blann A, Hay CR, Hollis S, Jayson MI: Von Willebrand factor, thrombomodulin, thromboxane, beta-thromboglobulin and markers of fibrinolysis in primary Raynaud's phenomenon and systemic sclerosis. Annals of the Rheumatic Diseases. 1996, 55: 122-127. 10.1136/ard.55.2.122.PubMed CentralView ArticlePubMedGoogle Scholar
- Pistorius MA, Planchon B, Schott JJ, Lemarec H: Heredity and genetic aspects of Raynaud's disease. Journal des Maladies Vasculaires. 2006, 31: 10-15.View ArticlePubMedGoogle Scholar
- Rychlik-Golema W, Mastej K, Adamiec R: The role of endothelin-1 and selected cytokines in the pathogenesis of Raynaud's phenomenon associated with systemic connective tissue diseases. International Angiology. 2006, 25: 221-227.PubMedGoogle Scholar
- Czupryniak A, Kaluzynska A, Nowicki M, Wiecek B, Bald E, Owczarek D: Raynaud's phenomenon and endothelial dysfunction in end-stage renal disease patients treated with hemodialysis. Kidney & Blood Pressure Research. 2005, 28: 27-31. 10.1159/000081059.View ArticleGoogle Scholar
- Lazzerini PE, Capecchi PL, Bisogno S, Cozzalupi M, Rossi PC, Pasini FL: Homocysteine and Raynaud's phenomenon: a review. Autoimmunity Reviews. 2010, 9: 181-187. 10.1016/j.autrev.2009.08.004.View ArticlePubMedGoogle Scholar
- LeRoy EC, Medsger TA: Raynaud's phenomenon: a proposal for classification. Clinical & Experimental Rheumatology. 1992, 10: 485-488.Google Scholar
- Harel L, Straussberg R, Rudich H, Cohen AH, Amir J: Raynaud's phenomenon as a manifestation of parvovirus B19 infection: case reports and review of parvovirus B19 rheumatic and vasculitic syndromes. Clinical Infectious Diseases. 2000, 30: 500-503. 10.1086/313712.View ArticlePubMedGoogle Scholar
- Toumbis-Ioannou E, Cohen PR: Chemotherapy-induced Raynaud's phenomenon. Cleveland Clinic Journal of Medicine. 1994, 61: 195-199.View ArticlePubMedGoogle Scholar
- Kruit WH, Eggermont AM, Stoter G: Interferon-alpha induced Raynaud's syndrome. Annals of Oncology. 2000, 11: 1501-1502. 10.1023/A:1026586629166.View ArticlePubMedGoogle Scholar
- Kallenberg CG: Raynaud's phenomenon as an early sign of connective tissue diseases. Vasa Supplementum. 1992, 34: 25-28.PubMedGoogle Scholar
- Sayre JW: Raynaud's disease presenting in a 5-month-old-male infant. Pediatrics. 1973, 52: 412-415.PubMedGoogle Scholar
- Cutolo M, Sulli A, Secchi ME, Paolino S, Pizzorni C: Nailfold capillaroscopy is useful for the diagnosis and follow-up of autoimmune rheumatic diseases. A future tool for the analysis of microvascular heart involvement?. Rheumatology. 2006, 45 (Suppl 4): iv43-46.PubMedGoogle Scholar
- Planchon B, Pistorius MA, Beurrier P, De Faucal P: Primary Raynaud's phenomenon. Age of onset and pathogenesis in a prospective study of 424 patients. Angiology. 1994, 45: 677-686. 10.1177/000331979404500802.View ArticlePubMedGoogle Scholar
- Meli M, Gitzelmann G, Koppensteiner R, Amann-Vesti BR: Predictive value of nailfold capillaroscopy in patients with Raynaud's phenomenon. Clinical Rheumatology. 2006, 25: 153-158. 10.1007/s10067-005-1146-1.View ArticlePubMedGoogle Scholar
- Allen E, Brown G: Raynaud's disease: A critical review of minimal requisites for diagnosis. Am J Med Sci. 1932, 183-187.Google Scholar
- Herrick AL: Pathogenesis of Raynaud's phenomenon. Rheumatology. 2005, 44: 587-596. 10.1093/rheumatology/keh552.View ArticlePubMedGoogle Scholar
- Duffy CM, Laxer RM, Lee P, Ramsay C, Fritzler M, Silverman ED: Raynaud syndrome in childhood. Journal of Pediatrics. 1989, 114: 73-78. 10.1016/S0022-3476(89)80604-3.View ArticlePubMedGoogle Scholar
- Singsen BH, Kornreich HK, Koster-King K, Brink SJ, Bernstein BH, Hanson V, Tan EM: Mixed connective tissue disease in children. Arthritis & Rheumatism. 1977, 20: 355-360.Google Scholar
- Walker ID: Thrombophilia in pregnancy. J Clin Pathol. 2000, 53 (8): 573-80. 10.1136/jcp.53.8.573.PubMed CentralView ArticlePubMedGoogle Scholar
- Calhoon MJ, Ross CN, Pounder E, Cassidy D, Manco-Johnson MJ, Goldenberg NA: High prevalence of thrombophilic traits in children with family history of thromboembolism. Journal of Pediatrics. 2010, 157: 485-489. 10.1016/j.jpeds.2010.03.031.View ArticlePubMedGoogle Scholar
- Carmel R, Green R, Rosenblatt DS, Watkins D: Update on cobalamin, folate, and homocysteine. Hematology. 2003Google Scholar
- Virdis A, Iglarz M, Neves MF, Amiri F, Touyz RM, Rozen R, Schiffrin EL: Effect of hyperhomocystinemia and hypertension on endothelial function in methylenetetrahydrofolate reductase-deficient mice. Arteriosclerosis, Thrombosis & Vascular Biology. 2003, 23: 1352-1357. 10.1161/01.ATV.0000083297.47245.DA.View ArticleGoogle Scholar
- Tawakol A, Forgione MA, Stuehlinger M, Alpert NM, Cooke JP, Loscalzo J, Fischman AJ, Creager MA, Gewirtz H: Homocysteine impairs coronary microvascular dilator function in humans. Journal of the American College of Cardiology. 2002, 40: 1051-1058. 10.1016/S0735-1097(02)02069-7.View ArticlePubMedGoogle Scholar
- Cheng T-T, Chiu C-K: Elevated homocysteine levels in patients with Raynaud's phenomenon secondary to systemic lupus erythematosus. Clinical Rheumatology. 2002, 21: 251-254. 10.1007/s10067-002-8291-6.View ArticlePubMedGoogle Scholar
- Kingma K, Wollersheim H, Thien T: Double-blind, placebo-controlled study of intravenous prostacyclin on hemodynamics in severe Raynaud's phenomenon: the acute vasodilatory effect is not sustained. Journal of Cardiovascular Pharmacology. 1995, 26: 388-393. 10.1097/00005344-199509000-00007.View ArticlePubMedGoogle Scholar
- Vinjar B, Stewart M: Oral vasodilators for primary Raynaud's phenomenon. Cochrane Database of Systematic Reviews. 2008, CD006687-Google Scholar
- van der Meer J, Wouda AA, Kallenberg CG, Wesseling H: A double-blind controlled trial of low dose acetylsalicylic acid and dipyridamole in the treatment of Raynaud's phenomenon. Vasa - Supplementum. 1987, 18: 71-75.PubMedGoogle Scholar
- Denton CP, Howell K, Stratton RJ, Black CM: Long-term low molecular weight heparin therapy for severe Raynaud's phenomenon: a pilot study. Clinical & Experimental Rheumatology. 2000, 18: 499-502.Google Scholar
- Ortensi A, Salsano F, Trinchi S, D'Orazi V, Pisarri S: Microsurgical distal sympathectomy in chronic vasospastic syndromes of the hand. International Surgery. 2005, 90: 88-92.PubMedGoogle Scholar
- Belch JJ, Ho M: Pharmacotherapy of Raynaud's phenomenon. Drugs. 1996, 52: 682-695. 10.2165/00003495-199652050-00006.View ArticlePubMedGoogle Scholar
- Schiopu E, Hsu VM, Impens AJ, Rothman JA, McCloskey DA, Wilson JE, Phillips K, Seibold JR: Randomized placebo-controlled crossover trial of tadalafil in Raynaud's phenomenon secondary to systemic sclerosis. Journal of Rheumatology. 2009, 36: 2264-2268. 10.3899/jrheum.090270.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.