RESUMEN
The TEMPI syndrome is a rare and acquired disorder characterized by 5 salient features, which compose its name: (1) telangiectasias; (2) elevated erythropoietin and erythrocytosis; (3) monoclonal gammopathy; (4) perinephric fluid collections; and (5) intrapulmonary shunting. Complete resolution of symptoms following treatment with plasma cell-directed therapy supports the hypothesis that the monoclonal antibody is causal and pathogenic. Understanding the basis of the TEMPI syndrome will depend on the identification of additional patients and a coordinated international effort.
Asunto(s)
Eritropoyetina/sangre , Enfermedades Pulmonares/patología , Paraproteinemias/patología , Policitemia/patología , Telangiectasia/patología , Humanos , Enfermedades Pulmonares/sangre , Enfermedades Pulmonares/terapia , Paraproteinemias/sangre , Paraproteinemias/terapia , Policitemia/sangre , Policitemia/terapia , Síndrome , Telangiectasia/sangre , Telangiectasia/terapiaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Mieloma Múltiple , Policitemia , Terapia Recuperativa , Telangiectasia , Dexametasona/administración & dosificación , Humanos , Lenalidomida/administración & dosificación , Masculino , Persona de Mediana Edad , Mieloma Múltiple/irrigación sanguínea , Mieloma Múltiple/tratamiento farmacológico , Policitemia/sangre , Policitemia/tratamiento farmacológico , Recurrencia , Síndrome , Telangiectasia/sangre , Telangiectasia/tratamiento farmacológicoAsunto(s)
Dermatomiositis/diagnóstico , Dedos , Dermatosis de la Mano/diagnóstico , Telangiectasia/diagnóstico , Preescolar , Dermatomiositis/sangre , Dermatomiositis/diagnóstico por imagen , Diagnóstico Diferencial , Femenino , Dermatosis de la Mano/sangre , Dermatosis de la Mano/diagnóstico por imagen , Humanos , Telangiectasia/sangre , Telangiectasia/diagnóstico por imagenAsunto(s)
Esclerodermia Difusa/sangre , Esclerodermia Limitada/sangre , Piel/patología , beta-Defensinas/sangre , Estudios de Casos y Controles , Fibrosis , Humanos , Esclerodermia Difusa/complicaciones , Esclerodermia Difusa/patología , Esclerodermia Limitada/complicaciones , Esclerodermia Limitada/patología , Telangiectasia/sangre , Telangiectasia/etiologíaRESUMEN
BACKGROUND: Anti-nuclear antibodies (ANA), anti-extractable nuclear antigens (ENA) and anti-dsDNA antibodies are often associated with cutaneous lupus erythematosus (CLE), with variable frequency depending on skin subtype. However, specific data based on large case-series on the pathogenetic, diagnostic and prognostic meaning of such autoantibodies are still lacking. OBJECTIVE: To characterize the correlations between CLE subtypes as well as LE-non-specific skin lesions and their autoantibody pattern. METHODS: Epidemiological, clinical and immunopathological data of 619 Italian patients with CLE and LE-non-specific skin lesions were analysed. Differences in age, sex, clinical features and autoantibody profile were evaluated in each LE subgroup. RESULTS: Anti-nuclear antibodies (P < 0.0001), anti-dsDNA (P < 0.0001), ENA (P = 0.001), anti-Sm (P = 0.001), anti-RNP (P = 0.004) and anti-histone (P = 0.005) antibodies were associated with SLE. A strong association between ANA (P < 0.0001) and anti-dsDNA (P < 0.0001) and female gender was also found: positive ANA and positive anti-dsDNA had a higher prevalence among females. Chronic CLE resulted to be negatively associated with ENA (OR = 0.51, P < 0.0001), anti-Ro/SSA (OR = 0.49, P < 0.0001) and anti-dsDNA (OR = 0.37, P < 0.0001). Intermittent CLE resulted to be negatively associated with ENA (OR = 0.50, P = 0.007) and ANA (OR = 0.61, P = 0.025). Subacute CLE resulted to be associated with ENA (OR = 5.19, P < 0.0001), anti-Ro/SSA (OR = 3.83, P < 0.0001), anti-Smith (OR = 2.95, P = 0.004) and anti-RNP (OR = 3.18, P = 0.007). Acute CLE resulted to be strongly associated with anti-dsDNA (OR = 6.0, P < 0.0001) and ANA (OR = 18.1, P < 0.0001). LE-non-specific skin lesions resulted to be significantly associated with systemic involvement. Livedo reticularis was significantly associated with ENA (P = 0.007) and anti-Ro/SSA (P = 0.036). Palpable purpura and periungual telangiectasia were significantly associated with ANA. CONCLUSION: According to our findings, some well-known associations between CLE subtypes and autoantibody profile were confirmed; moreover, specific association between autoantibodies and LE-non-specific skin lesions was highlighted. A strict association between anti-ENA and anti-Ro/SSA antibodies and livedo reticularis, ANA and palpable purpura, and ANA and periungual telangiectasia was evidenced.
Asunto(s)
Anticuerpos Antinucleares/sangre , Lupus Eritematoso Cutáneo/sangre , Lupus Eritematoso Cutáneo/epidemiología , Enfermedad Aguda , Adulto , Antígenos Nucleares/inmunología , Autoantígenos/inmunología , Enfermedad Crónica , Estudios Transversales , ADN/inmunología , Femenino , Histonas/inmunología , Humanos , Italia/epidemiología , Livedo Reticularis/sangre , Livedo Reticularis/epidemiología , Masculino , Persona de Mediana Edad , Púrpura/sangre , Púrpura/epidemiología , ARN Citoplasmático Pequeño/inmunología , Ribonucleoproteínas/inmunología , Factores Sexuales , Telangiectasia/sangre , Telangiectasia/epidemiologíaRESUMEN
OBJECTIVE: The aim was to investigate the pathogenesis of telangiectatic matting (TM) and identify possible risk factors. METHODS: This study had two parts. The clinical records of consecutive patients were retrospectively analysed to identify risk factors for TM. In the second part, the haemostatic and coagulation profile of the subset of patients with TM were analysed and compared with controls using standard coagulation tests, platelet function and a global assay of coagulation (rotational thromboelastometry, ROTEM). RESULTS: In 352 consecutive patients presenting to a phlebology practice, 25 patients had TM (7.1%). All 25 patients were female with the median age of 45 (27-57) years. A comprehensive medical history was taken. Among 27 possible risk factors assessed, statistically significant associations included recurrent epistaxis, easy bruising, hypersensitivity (eczema, hives, hay fever, and rhinitis), previous treatment with sclerotherapy or endovenous laser for lower limb veins, and a family history of telangiectasias. Variables not associated with TM included oral contraceptive intake, hormone replacement therapy, and age. The haemostatic and coagulation profile of 12 patients (6 male and 6 female) with TM did not differ significantly from those without TM. CONCLUSION: TM is associated with both hypersensitivity and a bleeding tendency. This study revealed no significant increase in the incidence of haemostatic abnormalities in patients with TM compared with the control group. Given the significant association with hypersensitivity disorders, the underlying mast cell hyper-reactivity may contribute to both hypersensitivity and a bleeding tendency and predispose patients to TM.
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Coagulación Sanguínea , Hipersensibilidad/sangre , Mastocitos , Microvasos/patología , Piel/irrigación sanguínea , Telangiectasia/sangre , Adulto , Femenino , Humanos , Hipersensibilidad/diagnóstico , Hipersensibilidad/epidemiología , Masculino , Persona de Mediana Edad , Pruebas de Función Plaquetaria , Estudios Prospectivos , Estudios Retrospectivos , Factores de Riesgo , Telangiectasia/diagnóstico , Telangiectasia/epidemiología , TromboelastografíaRESUMEN
BACKGROUND: Antimicrobial peptides have attracted much attention as a member of disease-associated molecules in systemic sclerosis (SSc), which is pathologically characterized by immune abnormalities, vasculopathy and tissue fibrosis. OBJECTIVE: To investigate the potential contribution of one of the antimicrobial peptide psoriasin to the development of SSc. METHODS: Psoriasin expression in the skin samples and sera derived from SSc patients and its correlation with clinical parameters were analysed. Psoriasin expression was evaluated by immunohistochemistry with skin samples from SSc patients and healthy controls. Serum levels of psoriasin were determined by enzyme-linked immunosorbent assay in 51 SSc patients and 19 healthy controls and assessed for the association with clinical symptoms. RESULTS: The expression of psoriasin was elevated in the epidermis of SSc lesional skin. Serum psoriasin levels were higher in SSc patients, especially in diffuse cutaneous SSc patients with disease duration of <6 years, than in healthy controls. With respect to clinical association, SSc patients with interstitial lung disease, telangiectasia and pitting scars had significantly augmented levels of serum psoriasin than those without each of these symptoms. In the subgroup of patients with interstitial lung disease, the elevation of serum psoriasin levels was associated with higher ground-glass opacity scores. Furthermore, serum psoriasin levels were decreased after the treatment with intravenous cyclophosphamide pulse as compared to baseline values. CONCLUSION: Our findings indicate a possible contribution of psoriasin to the development of clinical symptoms associated with vascular and epithelial abnormalities and inflammation in SSc, further supporting the roles of antimicrobial peptides in the SSc pathogenesis.
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Cicatriz/sangre , Enfermedades Pulmonares Intersticiales/sangre , Proteína A7 de Unión a Calcio de la Familia S100/sangre , Esclerodermia Sistémica/sangre , Telangiectasia/sangre , Adulto , Anciano , Estudios de Casos y Controles , Cicatriz/etiología , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Inmunosupresores/uso terapéutico , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/etiología , Masculino , Persona de Mediana Edad , Radiografía Torácica , Proteína A7 de Unión a Calcio de la Familia S100/metabolismo , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/metabolismo , Piel/metabolismo , Telangiectasia/etiologíaRESUMEN
UNLABELLED: Ma, Lan, Ying Chen, Guoen Jin, Yingzhong Yang, Qin Ga, and Ri-Li Ge. Vascular endothelial growth factor as a prognostic parameter in subjects with "plateau red face." High Alt Med Biol 16:147-153, 2015.--Some individuals living at high altitude on the Qinghai Plateau in China develop a red face called " Plateau Red Face" (PRF). It is characterized by telangiectasia of the cheeks, which become a unique ruddy color. It is more common in young females than males, subjects who have polycythemia are more susceptible to PRF, and its pathogenesis is unknown. The aim of this study was to investigate associations between PRF and levels of vascular endothelial growth factor (VEGF). METHODS: A total of 158 subjects (82 male and 76 female) residing at 4300 m and 140 subjects (73 male and 67 female) residing at 2260 m on the Qinghai Plateau, China, participated in this study. The determination and magnitude of PRF is evaluated by the dilation of veins on the face in the Qinghai chronic mountain sickness(CMS) score, established during the World Congress in 2004. Arterial O(2) saturation (Sao(2)), hemoglobin (Hb) concentration, pulmonary function tests, and serum concentration of VEGF (by ELISA) were measured in all participants. RESULTS: The occurrence of PRF was 32.9% (52/158) among subjects living at 4300 m and 15.7% (22/140) among those living at 2260 m. The levels of VEGF in PRF and non-PRF subjects were 399.9±115.6 pg/mL and 270.7±78.1 pg/mL, respectively (p<0.001) at 4300 m, and 244.4±109.0 pg/mL and 135.6±65.3 pg/mL, respectively (p<0.01) at 2260 m. However, comparing the levels of VEGF between the genders and ethnic groups at the same altitude, there were no significant differences between male and female both in Xining (p=0.12) and Maduo (p=0.18). There was also no significant difference between Tibetan and Han nationality in Xining (p=0.71), but In Maduo, the levels of VEGF in Han (351.70±122.62 pg/mL) were higher than that of Tibetan (300.20±102.89 pg/mL), and there was significant difference (p=0.01). Sao2 levels in PRF subjects (86.58±3.49) were lower than those of non-PRF subjects (88.04±3.68; p=0.018), while Hb was higher. Areas under receiver operator characteristic curve for diagnosis of PRF were 0.813, 0.679, and 0.373 for VEGF, Hb, and Sao(2), respectively. VEGF levels correlated positively with Hb levels both in Xining (r=0.367, p<0.001) and Maduo (r=0.319, p<0.001), and only negatively with Sao(2) levels in Maduo (r=-0.424, P<0.001) but not in Xining (r=0.125, p=0.141). CONCLUSION: Chronic hypoxemia may stimulate overproduction of angiogenic cytokine (VEGF), and this peptide may lead to formation of abnormal new vessels and development of congestion in mucosa and conjunctiva. Thus, VEGF may, at least in part, serve as a marker of the pathophysiologic trigger for PRF.
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Mal de Altura/sangre , Altitud , Telangiectasia/sangre , Factor A de Crecimiento Endotelial Vascular/sangre , Adulto , Mal de Altura/complicaciones , Biomarcadores/sangre , Mejilla/irrigación sanguínea , China , Enfermedad Crónica , Femenino , Hemoglobinas/análisis , Humanos , Masculino , Persona de Mediana Edad , Consumo de Oxígeno , Pigmentación , Policitemia/sangre , Policitemia/complicaciones , Pronóstico , Pruebas de Función Respiratoria , Telangiectasia/etiologíaAsunto(s)
Enfermedad Hepática en Estado Terminal/complicaciones , Telangiectasia/complicaciones , Telangiectasia/diagnóstico , Bebidas Alcohólicas , Diagnóstico Diferencial , Estrógenos/sangre , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Sustancia P/sangre , Telangiectasia/sangreRESUMEN
A distinctive mass in the liver in a two-month-old girl with elevated serum alpha-fetoprotein (AFP) level was diagnosed as telangiectatic focal nodular hyperplasia (FNH) after biopsy. The tumor spontaneously regressed and finally became no longer detectable by any imaging study within normal range of AFP. The nature of this novel entity and its management are discussed based on literature review.
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Hiperplasia Nodular Focal/patología , Hígado/patología , Telangiectasia/patología , Femenino , Hiperplasia Nodular Focal/sangre , Hiperplasia Nodular Focal/diagnóstico , Humanos , Lactante , Imagen por Resonancia Magnética , Telangiectasia/sangre , Telangiectasia/diagnóstico , alfa-Fetoproteínas/metabolismoRESUMEN
We have identified an autoantigen that is recognized by antibodies from an 18-year-old female with a history of recurrent infections who later in her clinical course developed Raynaud's phenomenon and telangiectasias. By indirect immunofluorescence (IIF), the index serum produced a unique cytoplasmic discrete speckled (CDS) staining pattern that partially colocalized with early endosome antigen 1 (EEA1) but not Golgi complex or other cytoplasmic organelles in HEp-2 cells. When HEp-2 cells were treated with 0.1 N HCl, the cytoplasmic speckled staining of the index serum was markedly decreased, suggesting that the reactive antigen was soluble. Western blot analysis showed a reactive approximately 97 kDa protein in a saline soluble protein preparation from HeLa cells. Mass spectrometric analysis of the excised 97 kDa band that was immunoprecipitated from HeLa cell extracts identified GRASP-1 as a possible target. The index serum and anti-GRASP-1 antibodies colocalized to structures in the cytoplasm of HEp-2 cells. Synthetic peptides representing the full-length GRASP-1 protein were used to identify reactive epitopes. Like many other cytoplasmic autoantigens, GRASP-1 has numerous coiled-coil domains throughout the protein with the exception of short segments at the amino and carboxyl terminus.
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Autoantígenos/inmunología , Proteínas Portadoras/inmunología , Endosomas/metabolismo , Adolescente , Secuencia de Aminoácidos , Especificidad de Anticuerpos/inmunología , Autoantígenos/metabolismo , Western Blotting , Proteínas Portadoras/genética , Línea Celular Tumoral , Endosomas/inmunología , Ensayo de Inmunoadsorción Enzimática , Mapeo Epitopo , Epítopos/genética , Epítopos/inmunología , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Proteínas del Choque Térmico HSP110 , Células HeLa , Proteínas de Choque Térmico/inmunología , Humanos , Ácido Clorhídrico/química , Inmunoprecipitación , Infecciones/sangre , Infecciones/inmunología , Infecciones/patología , Espectrometría de Masas , Proteínas de la Membrana/inmunología , Datos de Secuencia Molecular , Fragmentos de Péptidos/inmunología , Enfermedad de Raynaud/sangre , Enfermedad de Raynaud/inmunología , Enfermedad de Raynaud/patología , Recurrencia , Homología de Secuencia de Aminoácido , Telangiectasia/sangre , Telangiectasia/inmunología , Telangiectasia/patología , Proteínas de Transporte VesicularRESUMEN
Unilateral nevoid telangiectasia is a cutaneous condition consisting of congenital or acquired patches of superficial telangiectases in a unilateral linear distribution. Unilateral nevoid telangiectasia has been associated with elevations of blood estrogen levels and/or an increased number of estrogen receptors in the involved skin. We present a hepatitis-B carrier case with unilateral nevoid telangiectasia on the face and the right side of the neck; she had normal blood estrogen and a normal number of estrogen receptors in the involved skin.
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Dermatosis Facial/diagnóstico , Hepatitis B , Telangiectasia/diagnóstico , Diagnóstico Diferencial , Estrógenos/sangre , Dermatosis Facial/sangre , Dermatosis Facial/metabolismo , Dermatosis Facial/patología , Femenino , Humanos , Persona de Mediana Edad , Receptores de Estrógenos/metabolismo , Telangiectasia/sangre , Telangiectasia/metabolismo , Telangiectasia/patologíaAsunto(s)
Humanos , Adolescente , Adulto , Preescolar , Niño , Persona de Mediana Edad , Anciano , Hemorragia Gastrointestinal/clasificación , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/fisiopatología , Hemorragia Gastrointestinal/diagnóstico , Diverticulitis del Colon/diagnóstico , Diverticulitis del Colon/epidemiología , Diverticulitis del Colon/complicaciones , Diverticulitis del Colon/fisiopatología , Diverticulitis del Colon/sangre , Ectasia Vascular Antral Gástrica/etiología , Ectasia Vascular Antral Gástrica/diagnóstico por imagen , Ectasia Vascular Antral Gástrica/complicaciones , Ectasia Vascular Antral Gástrica/fisiopatología , Ectasia Vascular Antral Gástrica/terapia , Ectasia Vascular Antral Gástrica/sangre , Telangiectasia/etiología , Telangiectasia/fisiopatología , Telangiectasia/genética , Telangiectasia/sangre , Telangiectasia/terapia , Telangiectasia/cirugía , Hemangioma/fisiopatologíaRESUMEN
BACKGROUND: Leg telangiectasias are visible, ectatic dermal arteriols, capillaries, or veins with a diameter of 0.1-1 or 2 mm. Their origin is still not known and different opinions have been published. OBJECTIVE: In our study we were interested in the different colors of telangiectasias and we wanted to demonstrate whether a difference in blood gases is causing the difference in color between red and blue telangiectasias. METHODS: We measured a capillary astrup in 20 patients, who had red as well as blue telangiectasias on the lower limb. Therefore, we took two samples, one of a red and one of a blue telangiectasia. By this we measured the oxygen saturation and the carbon dioxide concentration of the samples. Furthermore, we introduced the appearance of telangiectasias in two rather newly developed techniques, such as high-frequency 20- and 50-MHz ultrasound and laser Doppler perfusion imaging (LDPI). RESULTS: Red telangiectasias of all 20 patients had an average oxygen concentration of 5.9 kPa, (range, 3.94-7.46 kPa); their average CO2 concentration was 5.45 kPa (range, 4.54-7.06 kPa). Blue telangiectasias had an average oxygen concentration of 5.11 kPa (range, 3.12-7.0 kPa); their average CO2 concentration was 6.07 kPa (range, 5.38-7.36 kPa). Statistically work-up with a paired student's t-test showed a higher oxygen saturation of the red telangiectasias and a higher carbon dioxide concentration of the blue vessels. CONCLUSION: As telangiectasias are assumed to be located in the capillary bed, the reason for differences in oxygenation could possibly be found in underlying physiological and anatomical principles of the capillary loops with the red telangiectasia representing the arterial loop of the capillary and the blue telangiectasia representing the venous loop of the capillary. With high frequency ultrasound and LDPI it is possible to get useful information for finding the underlying feeder veins, which "feed" the superficial telangiectasias. Injecting into the nutritional vessel telangiectases can potentially decrease the number of side effects and, may reduce the number of necessary injections.
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Oxígeno/sangre , Pigmentación de la Piel/fisiología , Telangiectasia/etiología , Adulto , Anciano , Análisis de los Gases de la Sangre , Dióxido de Carbono/sangre , Femenino , Humanos , Pierna/irrigación sanguínea , Masculino , Persona de Mediana Edad , Telangiectasia/sangre , Telangiectasia/diagnóstico por imagen , UltrasonografíaRESUMEN
We report a case where an acquired deficit in platelet aggregation was associated with the use of misoprostol and contributed to increased gastrointestinal blood loss. A 70-year-old man presented with chronic gastrointestinal blood loss secondary to widespread telangiectases. Investigations showed prolonged bleeding time and severely impaired platelet aggregation in vitro. Withdrawal of misoprostol resulted in resolution of the prolonged bleeding time and improvement in the platelet dysfunction. We conclude that misoprostol can lead to impaired platelet function and may exacerbate blood loss.
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Antiulcerosos/efectos adversos , Hemorragia Gastrointestinal/inducido químicamente , Misoprostol/efectos adversos , Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria/efectos de los fármacos , Anciano , Tiempo de Sangría , Enfermedad Crónica , Estudios de Seguimiento , Hemorragia Gastrointestinal/sangre , Humanos , Masculino , Pruebas de Función Plaquetaria , Telangiectasia/sangre , Telangiectasia/complicaciones , Telangiectasia/diagnósticoRESUMEN
BACKGROUND: Chronic venous insufficiency may be associated with lipodermatosclerosis or atrophie blanche. Coagulation abnormalities may be related to these cutaneous disorders. OBJECTIVE: Our purpose was to determine whether fibrinolytic abnormalities exist in patients with lipodermatosclerosis or atrophie blanche. METHODS: A case control study of patients with venous disease and atrophie blanche or lipodermatosclerosis was performed. Plasma levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in a resting and venous occluded state were measured. RESULTS: Plasma levels of PAI-1 were different between the two groups of patients. The lipodermatosclerosis group had significantly higher levels of PAI-1 in both the resting and venous occluded states (p < 0.001). Patients with atrophie blanche had milder elevations of PAI-1 in the resting and venous occluded state (p = 0.06). CONCLUSION: Fibrinolytic abnormalities are present in patients with venous disease. These abnormalities are different between patients with lipodermatosclerosis and patients with atrophie blanche.
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Fibrinólisis , Esclerodermia Localizada/fisiopatología , Enfermedades Cutáneas Vasculares/fisiopatología , Piel/patología , Insuficiencia Venosa/fisiopatología , Anciano , Análisis de Varianza , Atrofia , Trastornos de la Coagulación Sanguínea/fisiopatología , Estudios de Casos y Controles , Femenino , Fibrinólisis/fisiología , Humanos , Masculino , Persona de Mediana Edad , Inhibidor 1 de Activador Plasminogénico/sangre , Descanso , Esclerodermia Localizada/sangre , Enfermedades Cutáneas Vasculares/sangre , Telangiectasia/sangre , Telangiectasia/fisiopatología , Tromboflebitis/sangre , Tromboflebitis/fisiopatología , Activador de Tejido Plasminógeno/sangre , Úlcera Varicosa/sangre , Úlcera Varicosa/fisiopatología , Insuficiencia Venosa/sangreRESUMEN
A previously healthy 32-year-old man presented with recurrent exercise induced painless gross hematuria and hematospermia. An extensive evaluation demonstrated classic von Willebrand's disease associated with vascular telangiectasia of the prostate gland as the locus of hemorrhage. The bleeding resolved spontaneously and without recurrence. The coexistence of von Willebrand's disease and vascular telangiectasia has been described previously, although it is a rare occurrence. However, a review of the English literature revealed no report of vascular telangiectasia involving the prostate gland, and therefore is the subject of this report. The prostate gland now should be added to the list of viscera associated with vascular telangiectasia and von Willebrand's disease.