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n e w e ng l a n d j o u r na l
m e dic i n e
case records of the massachusetts general hospital
Founded by Richard C. Cabot Eric S. Rosenberg, m.d., Editor Jo-Anne O. Shepard, m.d., Associate Editor Sally H. Ebeling, Assistant Editor
Nancy Lee Harris, m.d., Editor Alice M. Cort, m.d., Associate Editor Emily K. McDonald, Assistant Editor
Case 36-2013: A 38-Year-Old Woman with Anemia and Thrombocytopenia
Douglas E. Wright, M.D., Ph.D., Rachel P. Rosovsky, M.D., M.P.H., and Mia Y. Platt, M.D., Ph.D.
Pr e sen tat ion of C a se
From the Departments of Medicine (D.E.W., R.P.R.) and Pathology (M.Y.P.), Massachusetts General Hospital, and the Departments of Medicine (D.E.W., R.P.R.) and Pathology (M.Y.P.), Harvard Medical School — both in Boston.
N Engl J Med 2013;369:2032-43. DOI: 10.1056/NEJMcpc1215972
Copyright © 2013 Massachusetts Medical Society.
Dr. Joanna Lopez (Medicine): A 38-year-old woman was admitted to this hospital because of anemia and thrombocytopenia. The patient had been well until approximately 3 months before admission, when fatigue, malaise, and light-headedness developed that she attributed to a viral illness. Three weeks before admission, fatigue worsened, and dyspnea on exertion, bruising on the legs, dark urine, and headache developed. She reported that she "felt like staying in a bed all day" and needed assistance with showering. Two days before admission, she went to another hospital. The physical examination was reportedly normal, as were the results of coagulation tests. Screening for antibodies to the human immunodeficiency virus (HIV) and a rapid plasma reagin test were negative; other test results are shown in Table 1. She was admitted to the other hospital. Examination of the peripheral-blood smear reportedly revealed normal morphologic features of the white cells, a reduced platelet count, spherocytes, and polychromatic red cells. A direct antiglobulin test (Coombs' test) was positive, and warm-reacting and cold-reacting autoantibodies were reportedly present. Results of serum and urinary protein electrophoresis were normal. Glucocorticoids (methylprednisolone at a dose of 150 mg twice daily for 2 days, followed by prednisone at a dose of 70 mg twice daily) were administered, as were ondansetron and folate, but the patient's condition did not improve (Table 1). Computed tomographic (CT) scans of the abdomen and pelvis, obtained after the intravenous administration of contrast material, were normal. On the second night, hypotension developed but improved after the intravenous administration of fluids. On the third day, the hematocrit was 16.8%. One unit of packed red cells was transfused, and pantoprazole was administered. The patient was transferred to this hospital because of difficulty finding additional red-cell units that were compatible with her antibody screen. On admission, the patient reported a weight loss of 2.3 kg during the previous week, intermittent blurred or double vision in both eyes, and for the previous 3 months, transient vesicular lesions on the thighs that resolved spontaneously
n engl j med 369;21 nejm.org november 21, 2013
The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
a urine culture grew more than 100. and the symptoms resolved. mean corpuscular hemoglobin. chills. The blood type was O. epistaxis. globulin. alkaline phosphatase.org on January 22. magnesium. Medications at home included bupropion. folate. She had no known allergies. Transfusion of 1 unit of leukoreduced red cells was begun. on the contralateral side. however. She did not have hematuria. or they may be unrelated. albumin. She had a history of depression. her siblings and child were healthy. lightheadedness. and her mother had diabetes mellitus. phosphorus. moved to the United States more than 10 years earlier. For personal use only. burning. These four events may be episodes of a chronic illness that is related to the present illness. or hematochezia. calcium. drink alcohol. melena. and the systolic blood pressure fell from 94 to 84 mm Hg within 15 minutes. she had had a hysterectomy at 22 years of age because of metrorrhagia after a cesarean section. The illness that occurred 3 years before admission. On examination. and blood cultures were sterile. which had gradually resolved spontaneously. with dyspnea. the patient's blood pressure was 105/55 mm Hg. Her father had hyperthyroidism. Douglas E. light-headedness.g. the prothrombin-time international normalized ratio. anemia (a hematocrit 6 years before admission was reportedly normal). 2013 The New England Journal of Medicine Downloaded from nejm. folate. The culture of the lesion on the right thigh revealed herpes simplex virus type 2 (HSV-2). or use illicit drugs. such as bleeding disorders.case records of the massachuset ts gener al hospital within 2 or 3 days. total protein. and an illness consisting of dyspnea. Additional test results are shown in Table 1. as were the prothrombin time. Testing for partial-thromboplastin time to detect a lupus anticoagulant was negative. light-headedness. C-reactive protein. A swab of the lesion on the right thigh was sent for culture. polychromatocytes. is highly unusual1 and would warrant a diagnostic workup for a bleeding disorder. Approximately 3 years earlier. abdominal pain. or a major depressive disorder. 2014. Four noteworthy events in the history are epistaxis during childhood. and weight loss. She was born in South America. arthralgias. and during childhood and pregnancy. results of renal-function tests. a multivitamin.org november 21. she had had a similar illness. The red-cell indexes (mean corpuscular volume. vomiting. She had mild conjunctival icterus and a single vesicular lesion (1 cm in diameter) with an erythematous base on the posterior right thigh. predominantly normal platelets. and an unintentional weight loss of 18 kg. Rh-positive. The administration of prednisone. very few metamyelocytes. a cesarean section complicated by metrorrhagia that required hysterectomy. and the other vital signs and oxygen saturation were normal. and facial flushing occurred. No other uses without permission. Diagnostic tests were performed. However. a severe nonmalignant systemic illness. amylase. Urinalysis revealed 3+ urobilinogen and was otherwise normal. Another attempt was made. If she previously had a nonmalignant systemic illness. chest pain. light-headedness. she probably would not have recovered without treatment. epistaxis during pregnancy at 21 years of age. nausea. but without more detailed information. with dyspnea. and weight loss. and a weight loss of 18 kg that occurred 3 years before admission. myalgias. Examination of the peripheral-blood smear revealed macrocytes. is also worrisome and raises concern that the patient has a malignant disease. and blood levels of electrolytes. and worked with children. and no schistocytes or malignant cells. Wright: An overview of the patient's medical history provides clues to the cause of the present illness. She had recently traveled to Central America and the Caribbean. 2033 n engl j med 369. other test results are shown in Table 1. after the infusion of a few milliliters. The remainder of the examination was normal.21 nejm. She did not smoke. and occasionally flaxseeds. fevers. a cesarean section followed by metrorrhagia that is severe enough to require hysterectomy. but pain and burning developed immediately at the site of the infusion. dysuria.000 mixed flora. these are not helpful clues. and bupropion were continued. lipase. Copyright © 2013 Massachusetts Medical Society. and mean corpuscular hemoglobin concentration) were normal. an antibody screen (indirect antiglobulin test) and a direct antiglobulin test were positive. pain. Differ en t i a l Di agnosis Dr. If she previously had a malignant tumor that caused dyspnea. All rights reserved. Epistaxis during childhood and pregnancy can result from serious chronic diseases. in the absence of complications during the labor or the surgery. and vitamin B12. microspherocytes. and management decisions were made.. The transfusion was stopped. . it could have been either a discrete illness that resolved and would not be expected to recur (e.
52 <10 16–199 70–110 0. No other uses without permission.000 11.0–16.200. A diagnoTable 1.* Reference Range. First Admission.1 14.000– 5. As we analyze the present illness.3 9–32 7–30 110–210 30–160 230–404 10–200 Negative Negative at 1:10 dilution 59 77 461 4. on Admission 20..9 353 1.000 3.0 12.00–0.500 85 6 5 2 2 1 67. by PCR Antibodies to double-stranded DNA <6 140 2.7 10.000 Other Hospital. by report 53.0 0.0 0. Adults† 36. Copyright © 2013 Massachusetts Medical Society.7 104 (mg/liter) Fibrin-degradation products (µg/ml) Haptoglobin (mg/dl) Glucose (mg/dl) Bilirubin (mg/dl) Total Direct Indirect Aspartate aminotransferase (U/liter) Alanine aminotransferase (U/liter) Lactate dehydrogenase (U/liter) Iron (µg/dl) Total iron-binding capacity (µg/dl) Ferritin (ng/ml) Epstein–Barr virus DNA.000.3 (manual) 87.4 36 52 484 444 176 229 775 Positive 8 IU/ml§ Negative at 1:10 dilution <6 112 1.4 4. on Admission 19.000 122.5 0–17 161–393 0.0–0.000 2. .4 7.5 0.21 nejm. A chronic illness might explain the epistaxis during childhood and pregnancy and the bleeding after a cesarean section. Laboratory Data.g. 2013 The New England Journal of Medicine Downloaded from nejm.2 27.5 10.9 11.25 <10 Elevated. For personal use only.1 7. Day 2 20. 2014. we must remember that the patient may have an underly- Variable Hematocrit (%) Hemoglobin (g/dl) White-cell count (per mm3) Differential count (%) Neutrophils Band forms Lymphocytes Monocytes Myelocytes Metamyelocytes Nucleated red cells (per 100 white cells) Platelet count (per mm3) Erythrocyte count (per mm3) Red-cell distribution width (%) Reticulocytes (%) Erythrocyte sedimentation rate (mm/hr) Fibrinogen (mg/dl) D-Dimer Other Hospital.5–14.3 138 349 416 <300‡ 2034 n engl j med 369.000 22.200 79 8 10 2 1 7 This Hospital.5 10.000 4.000 20. intermittent hemolytic anemia).5 0.000– 400.450.0–1.The n e w e ng l a n d j o u r na l of m e dic i n e pneumonia) or an episode of a relapsing and remitting illness (e.5–2.200.0–46.300 This Hospital.org on January 22.org november 21. Days 7–9 32.0 sis of major depressive disorder could be made only after a thorough search for a systemic illness has been performed.0 4500–11.000 40–70 0–10 22–44 4–11 0 0 0 150. All rights reserved.
Days 7–9 10.9 Positive at 1:40 and 1:160 dilutions. 2013 The New England Journal of Medicine Downloaded from nejm.21 nejm. To convert the values for iron and iron-binding capacity to micromoles per liter. Adults† 0. and dark urine. the patient noted malaise. For personal use only. MPL IgM phospholipid.case records of the massachuset ts gener al hospital Table 1. ing relapsing and remitting condition associated with a bleeding disorder. including the patient population and the laboratory methods used.90 ≤0. light-headedness. by quantitative PCR (copies per ml) Anticardiolipin IgM antibodies (MPL units) Anticardiolipin IgG antibodies (GPL units) Antinuclear antibodies Hepatitis B surface antibodies Hepatitis B surface antigen Hepatitis B core antibodies Hepatitis A total antibodies Hepatitis A IgM antibodies Hepatitis C antibodies Hepatitis B e antigen Hepatitis B e antibodies Hepatitis B nucleic acid IgM antibodies to Epstein–Barr virus VCA IgG antibodies to Epstein–Barr virus VCA Antibodies to Epstein–Barr virus nuclear antigen Heterophile antibodies Varicella IgG antibodies Mycoplasma pneumoniae IgG antibody index M. (Continued. GPL IgG phospholipid. ‡ PCR assay for Epstein–Barr virus DNA detects levels ranging from 300 to 150.9) 0. PCR polymerase chain reaction. 2014.05551.7 (AI ref 0. and transient vesicular lesions on the thighs. No other uses without permission. Copyright © 2013 Massachusetts Medical Society.90 Negative Nonreactive Nonreactive None detected 31.71 0. on Admission This Hospital.6 14.99 0. All rights reserved.0–19.9 (AI ref 0. Over a period of 3 months.org on January 22. bruising.89 Positive at 1:20 dilution Negative at 1:20 dilution Variable Antibodies to SSA (Ro) (OD units) Antibodies to SSB (La) (OD units) Antibodies to smooth muscle Antimitochondrial antibodies Cytomegalovirus DNA.81 Other Hospital. visual symptoms. each of these symptoms is nonspecific. on Admission Other Hospital. multiply by 0.1.org november 21. homogeneous pattern Reactive Negative Positive Positive Negative Negative Negative Negative Negative Negative Positive Positive Negative Positive 1. They may therefore not be appropriate for all patients. § The following reference ranges for antibodies to double-stranded DNA are used at the other hospital: a value lower than 5 IU per milliliter is negative. multiply by 0.) Reference Range. dyspnea. but nonspecific symptoms must be evaluated in terms of their severity and in the context of concurrent symp2035 n engl j med 369.0–19.000 copies per milliliter.99 Negative at 1:20 dilution Negative at 1:20 dilution None detected 0–15 0–15 Negative at 1:40 and 1:160 dilutions Nonreactive Nonreactive Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative ≤0. headache. multiply by 17. To convert the values for glucose to millimoles per liter. . The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results.0–0. When considered individually.9) This Hospital. a value of 5 to 9 IU per milliliter is equivocal. OD optical density. First Admission. followed by severe fatigue. pneumoniae IgM antibody index * AI ref denotes antibody index reference range.1791. To convert the values for bilirubin to micromoles per liter.0–0. and VCA viral capsid antigen.27 8. and a value greater than 9 IU per milliliter is positive. Day 2 3. † Reference values are affected by many variables.
G6PD glucose-6-phosphate dehydrogenase. low level of G6PD activity Spherocytes Glycosylphosphatidylinositol-linked proteins on flow cytometry Extravascular Intravascular * DIC denotes disseminated intravascular coagulation. with the exception of paroxysmal nocturnal hemoglobinuria.g. thalassemias.4 and Major Site of Hemolysis Extravascular Extravascular Intravascular Extravascular Intravascular Extravascular Intravascular Extravascular Intravascular Extravascular Intravascular Findings on Peripheral-Blood Smear and Laboratory Tests Spherocytes. elevated liver-enzyme levels. patients with burns) Drug-induced immune hemolytic anemia Hemolytic transfusion reactions Hypersplenism Hypotonic lysis Infection (e. Table 2.. bongo drummers. acute and chronic DIC are associated with elevated levels of fibrin-degradation products and d-dimer Oxidant injury (due to exposure to dapsone.g. abnormal genetic-test results In G6PD deficiency: bite cells. blister cells. but the diagnosis must be confirmed by laboratory data. pyruvate kinase deficiency) Defect in the red-cell membrane Hereditary spherocytosis Paroxysmal nocturnal hemoglobinuria Extravascular Intravascular Intravascular Intravascular Extravascular Extravascular Schistocytes Red-cell agglutination Erythrophagocytosis Target cells.* Cause Associated with intrinsically normal red cells Autoimmune hemolytic anemia Complement-induced lysis Direct trauma (seen in runners.org november 21.. and the haptoglobin level was low.The n e w e ng l a n d j o u r na l of m e dic i n e toms. acute DIC is associated with abnormal prothrombin time and partial-thromboplastin time. nucleated red cells. HELLP syndrome. dyspnea. babesia. sickle cell anemia. reticulocytes.. a diagnosis of hemolytic anemia can be made. For personal use only. thrombotic thrombocytopenic purpura. hypertensive emergency) Hemolytic Anemia Hemolytic anemia (anemia that is principally due to the shortened survival of red cells)2 has numerous causes (Table 2). On presentation at the other hospital. The constellation of fatigue. On the basis of these results. † Disorders associated with intrinsically abnormal red cells are inherited.. G6PD deficiency. positive direct antiglobulin test Spherocytes Red-cell inclusion bodies Red-cell ghosts Schistocytes (i. No other uses without permission..g. and dark urine is consistent with hemolytic anemia and a bleeding disorder. All rights reserved. . Selected Causes of Hemolytic Anemia. abnormal hemoglobin electro phoresis.g. malaria.org on January 22. easy bruising. 2014. positive direct antiglobulin test Hemoglobinuria. the patient had a hematocrit of 20%. 2013 The New England Journal of Medicine Downloaded from nejm. Levels of lactate dehydrogenase and indirect bilirubin were elevated. We have already found clues in the history to suggest a diagnosis. and HELLP hemolysis. which is caused by an acquired defect in the red-cell membrane. phenazopyridine. hemolytic–uremic syndrome.21 nejm. helmet cells). myoglobinuria Spherocytes. DIC. aniline dyes) Shearing by prosthetic heart valves Cold-agglutinin disease (in some cases) Paroxysmal cold hemoglobinuria Associated with intrinsically abnormal red cells† Hemoglobinopathy (e.e. and a low platelet count. Copyright © 2013 Massachusetts Medical Society. The most striking laboratory data in this case are consistent with hemolytic anemia (most likely autoimmune hemolytic anemia) and thrombocytopenia. unstable hemoglobins) Metabolic deficiency (e.3 2036 n engl j med 369. bartonella) Clostridial sepsis Infusion of intravenous immune globulin Microangiopathic hemolytic anemia (e.
g. All rights reserved. malignant diseases (especially chronic lymphocytic leukemia). the presence of spherocytes but no schistocytes on the peripheral-blood smear. dyspnea. By a process of elimination and on the basis of the history and laboratory-test results.11 at least 4 of 11 criteria must be met for a diagnosis of SLE to be made. a culture of the vesicular lesion on the thigh was positive for HSV-2. spherocytes form. In this patient. and thus it is unlikely that she has intrinsically abnormal red cells. the positive direct antiglobulin test with warm-reacting and cold-reacting auto- According to American College of Rheumatology guidelines. This patient has laboratory evidence consistent with intravascular hemolysis (e. or both. metabolic machinery. spherocytes and dark urine) and may also have extravascular hemolysis (e. haptoglobin levels can be low and unconjugated bilirubin levels can be elevated in patients with intravascular hemolysis. As compared with the uncontrolled lysis of red cells that occurs during intravascular hemolysis. and infections of red cells. If intravascular hemolysis is incomplete. I think that SLE is the underlying cause of autoimmune hemolytic anemia in this patient. Autoimmune hemolytic anemia can be idiopathic or associated with connective-tissue disease (especially systemic lupus erythematosus [SLE]). drug use (especially the use of cephalosporins and piperacillin). and normal results on coagulation tests are findings consistent with autoimmune hemolytic anemia. Nothing in this patient's history suggests that she has an inherited red-cell disorder. but some of the test results are inconsistent. binding to haptoglobin and reducing hapto globin levels. The transience of the lesions on the patient's thigh is more consistent with recurrent HSV infection than with primary infection. Hemolytic anemia associated with normal red cells can be caused by the destruction of red cells by antibodies or complement. 3 of the criteria have been met: the presence 2037 n engl j med 369. No other uses without permission. the breakdown of hemoglobin to bilirubin.9 Neither primary nor recurrent HSV infection has been implicated in the development of autoimmune hemolytic anemia. However. . and direct antiglobulin test are helpful in determining the cause of hemolytic anemia (Table 2).g. hemoglobin is released into the blood.. Copyright © 2013 Massachusetts Medical Society. In this patient. or a previous transfusion or transplantation. results of serologic and DNA testing for viruses and mycoplasma did not suggest an infectious cause of autoimmune hemolytic anemia. In this case. common variable immunodeficiency). the most plausible interpretation of the serologic and DNA test results for HBV is a resolved infection.8 Finally. iron. immunodeficiency (e.4 and disorders associated with abnormal red cells are nearly all inherited. the shearing of red cells in the microvasculature or by prosthetic heart valves.10. Systemic Lupus Erythematosus The peripheral-blood smear. The second question to ask when considering the cause of hemolytic anemia is whether hemolysis is occurring within the blood vessels or outside the blood vessels (in the liver. since other test results for EBV are consistent with past infection.org november 21. Viral and mycoplasma infections must be considered as possible causes of autoimmune hemolytic anemia. 2013 The New England Journal of Medicine Downloaded from nejm. and dark urine. 2014. she reportedly had a normal hematocrit 6 years before presentation.5 This patient was not taking any of the drugs that have been implicated in antibodymediated hemolytic anemia. For personal use only. and she had not undergone a blood transfusion immediately before the present illness. or cell membranes.21 nejm. The first question to ask when considering the cause of hemolytic anemia is whether the red cells are intrinsically normal or abnormal (Table 2).. Autoimmune Hemolytic Anemia antibodies. elevated levels of indirect bilirubin).7 A second inconsistency is that testing for hepatitis B virus (HBV) surface antibody was initially nonreactive and later reactive. coagulation tests.. viral infection.g. For instance.6 Nothing in her history suggests immunodeficiency. the initial result was likely to be a false positive result. During intravascular hemolysis.org on January 22. or bone marrow) (Table 2). spleen.case records of the massachuset ts gener al hospital such a diagnosis is consistent with the patient's disabling fatigue. testing for Epstein–Barr virus (EBV) DNA was initially positive but was negative on repeat testing. extravascular hemolysis. extravascular hemolysis is a more controlled process that involves phagocytosis of red cells by macrophages. and unbound alpha-globin dimers and beta-globin dimers cause both plasma and urine to turn reddish-brown. She had no history of solid-organ or stem-cell transplantation. and the release of unconjugated bilirubin. Abnormal red cells may break down because of problems with their hemoglobin. and carbon monoxide into the blood.
An antibody screen (indirect antiglobulin test) was performed to detect unexpected antibodies to red-cell antigens that are not part of the ABO blood group..The n e w e ng l a n d j o u r na l of m e dic i n e of a hematologic disorder (i. half the cases were primary. with or without the presence of a cold-reacting autoantibody. and incubated at 37°C. possibly due to systemic lupus erythematosus. they usually bind carbohydrate antigens and are very rarely associ- n engl j med 369. Rosovsky. W R IGH T 'S DI AGNOSIS Autoimmune hemolytic anemia and thrombocytopenia (Evans syndrome). the transiently positive tests for antibodies to SSA (Ro). Cl inic a l Di agnosis Autoimmune hemolytic anemia and thrombocytopenia (Evans syndrome).000 per cubic millimeter on presentation and rose to a maximum count of 122. severe bleeding after a cesarean section.21 nejm. Warm-reacting autoantibodies are optimally reactive at 37°C. the bleeding during and after pregnancy. Copyright © 2013 Massachusetts Medical Society. These findings were consistent with the presence of a warm-reacting autoantibody. The patient had not only autoimmune hemolytic anemia but also thrombocytopenia. . an immunologic disorder (i.e. and a robust reticulocyte response that suggests healthy bone marrow. Mia Y. complement. At the time of this hospitalization.000 per cubic millimeter after treatment with glucocorticoids. The red cells were washed and incubated with an antiglobulin reagent containing anti-IgG and anti-C3d. Rh-positive. A direct antiglobulin test was performed to detect bound antibody. would you tell us your impression when you saw the patient? Dr. For personal use only.e. taken together with the fluctuating course of illness. a specimen of the patient's blood was sent to the blood bank for routine typing and screening. hemolytic anemia. in which bound antibody was stripped from the red cells. 2014. An antiglobulin reagent containing anti-IgG was added. Patients with autoimmune hemolytic anemia and immune thrombocytopenic purpura. the platelet count was 53. my diagnosis in this case is the Evans syndrome. with reticulocytosis and thrombocytopenia [a platelet count of <100. 2013 The New England Journal of Medicine Downloaded from nejm. Rachel P. we agreed with Dr. each with a known antigenic composition. The resultant eluate was reactive to an extended panel of reagent red cells in an indirect antiglobulin test.13 The Evans syndrome can be primary (i. DR . and agglutination was assessed. possibly associated with SLE. The direct antiglobulin test was strongly positive for both IgG and complement. No other uses without permission.org november 21. and an abnormal titer of antinuclear antibodies (ANA).14 In summary. they usually bind protein antigens and may be associated with hemolysis. immunodeficiencies.e. All rights reserved. we wonder whether her previous bleedingrelated events are associated with the current thrombocytopenia. and after centrifugation. Dr. and many of the secondary cases were associated with SLE. in 1951..000 per cubic millimeter]). a positive test for antiphospholipid antibodies). rheumatology consultants did not think 2038 Pathol o gic a l Discussion Dr. Follow-up testing included an elution step. agglutination of the red cells was assessed. and the presence of autoimmune hemolytic anemia. idiopathic) or associated with SLE or other immune disorders. or lymphoproliferative disorders. A plasma sample was mixed with a screening panel of three type-O reagent red cells. and whether the thrombocytopenia and the autoimmune hemolytic anemia are causally related.org on January 22. or both were described by Evans and Duane in 194912 and by Evans et al. However. The blood type was O. Platt: On the day of admission. neutropenia.. In a 2009 review of 68 cases. We cannot answer the first question without more information from her history. cold-reacting autoantibodies are optimally reactive at 0 to 4°C. and recent bruising. Nancy Lee Harris (Pathology): Dr. These 3 criteria. the patient has evidence of active immune-mediated red-cell destruction. I think that the thrombocytopenia and the autoimmune hemolytic anemia are causally related. normal coagulation indexes and markers of fibrinolysis. In contrast. The antibody screen showed reactivity to all three cells in the screening panel. Thrombocytopenia that the patient met the criteria for an underlying rheumatologic disease. In light of these factors. Wright's diagnosis of the Evans syndrome. She had epistaxis during childhood and pregnancy. D OUGL A S E . Rosovsky: When we saw the patient. indicate that the patient most likely has SLE or a similar condition. or both on the patient's red cells.
Copyright © 2013 Massachusetts Medical Society. immunodeficiencies. the treatment strategy is largely based on the strategy for isolated immune thrombocytopenic purpura or autoimmune hemolytic anemia. and headaches. we are aware of no randomized. most are autoimmune diseases. This patient received a transfusion when the hematocrit was at a nadir of 16. the titer of coldreacting autoantibodies. who have low blood counts. Secondary Causes of the Evans Syndrome. We know of no randomized clinical trials showing the effectiveness of glucocorticoids in the treatment of the Evans syndrome. For personal use only. spontaneous remissions or exacerbations of the disease can occur. All rights reserved. Cold-reacting autoantibodies associated with hemolytic anemia usually have a broad thermal range that enables them to bind target antigens at near-physiologic temperatures. prednisone is subsequently tapered at a rate of 10 mg per week. No other uses without permission. 2014. but glucocorticoids have remained the standard treatment option since they were first described for this indication by Dameshek et al. or infections (Table 3). there is a lack of high-quality research. controlled trials and only a few prospective trials and long-term follow-up studies.8% and she had dyspnea. Rosovsky: Identifying a secondary cause of the Evans syndrome in this patient could help determine the treatment strategy. was negative. such as this one. Finally. the treatment of asymptomatic patients with low counts is not so straightforward and depends on the choices of the patient and clinician.case records of the massachuset ts gener al hospital ated with hemolysis. and so we are left with a diagnosis of idiopathic Evans syndrome. even among different episodes in an individual patient. and the response to treatment varies. There are no established criteria on how to define a complete response. It is appropriate and usually necessary to treat symptomatic patients. First-line Treatment for Patients with the Evans Syndrome One of the first questions to ask before treating a patient with the Evans syndrome is whether a red-cell transfusion is required. Finding an effective treatment for idiopathic Evans syndrome can be difficult for several reasons. Second. Secondary causes have been reported in 50% of patients14. This decision is based on the severity of the anemia and the age and clinical condition of the patient. Autoimmune diseases Systemic lupus erythematosus Antiphospholipid antibody syndrome Sjögren's syndrome Infections Cytomegalovirus Influenza A Parvovirus Hepatitis Varicella Nocardia Leishmaniasis Epstein–Barr virus Malignant diseases Chronic lymphocytic leukemia B-cell and T-cell non-Hodgkin's lymphomas Plasma-cell myeloma Monoclonal gammopathy of undetermined significance Amyloidosis Chronic myelomonocytic leukemia Kaposi's sarcoma Pancreatic adenocarcinoma Immunodeficiency disorders Common variable immunodeficiency IgA deficiency Other Graves' disease Dermatomyositis Pregnancy Guillain–Barré syndrome Ulcerative colitis Bronchiolitis obliterans with organizing pneumonia Castleman's disease Acute inflammatory demyelinating polyradiculoneuropathy Celiac disease Discussion of M a nagemen t Dr.org november 21. in the Journal in 1950. Table 3. 2013 The New England Journal of Medicine Downloaded from nejm. First. we evaluated for cold-reacting autoantibodies.21 nejm.org on January 22. In this case. severe fatigue. as long as the hemato2039 n engl j med 369. .14-18 Prednisone is usually administered (at a dose of 1 to 2 mg per kilogram of body weight per day) until the hematocrit is higher than 30% or the hemoglobin level is higher than 10 g per deciliter. In view of the patient's unusual reaction of acute pain during the transfusion and the report by the other hospital of the presence of a cold-reacting autoantibody. lymphomas. obtained at a 1:16 dilution at 4°C. there was no clear evidence of an associated systemic disorder.
SSB (La). however. We are aware of no studies of single-agent IVIG.14 Preoperative vaccinations. including pneumococcal. Copyright © 2013 Massachusetts Medical Society. sepsis. cyclosporine) Chemotherapy (vincristine. including tests for antibodies to SSA (Ro). Adverse events include but are not limited to reactions to infusion. Risks associated with the procedure include death and the usual effects associated with general anesthesia.21 nejm.25 In small case series of the Evans syndrome (autoimmune hemolytic anemia and immune thrombocytopenic purpura). and bilateral knee effusions with no crystals (determined by patellar arthrocentesis) developed. HBV reactivation. and a lifelong risk of infections. are necessary. 8 mg per deciliter [normal range.20 In this patient.16. and testing for cryoglobulins was negative.org on January 22. If the hematocrit is still below 30% after 1 month. Second-line Treatment for Patients with the Evans Syndrome Second-line treatment can include IVIG. cyclophosphamide) Azathioprine Bone marrow transplantation crit and hemoglobin level are stable. has been reported to be an effective second-line treatment for the Evans syndrome in single case reports and case series. and parvovirus) was negative. she had a relapse 3 months later. After the appropriate vaccinations were administered to the patient. Then. in view of the refractory nature of the disease. Intravenous immune globulin Therapeutic antibodies (rituximab) Splenectomy Danazol Immunosuppressive agents (mycophenolate mofetil. but after two infusions. After she was discharged.21-24 Second and third remissions have been seen with repeated doses. therapeutic antibodies. 16 to 38]). an immediate response is usually produced but can be transient. the hematocrit was 14% and the patient was symptomatic. 2013 The New England Journal of Medicine Downloaded from nejm. smooth muscle. cytomegalovirus. low levels of complement (C3 level. infections.14. The duration of response ranges from 11 weeks to 42 months. Testing for infectious diseases (HIV. and Haemophilus influenzae vaccinations. the main goal is to slowly taper the medication over a period of several months and eventually discontinue it. Thyrotropin levels and results of coagulation tests and serum protein electrophoresis were normal. Second-line Therapies for the Evans Syndrome. Splenectomy Rituximab. 23. The role of splenectomy in the treatment of the Evans syndrome is not clearly established. while she was still taking prednisone. elevated levels of β2-glycoproteins (>100 U per milliliter [normal value.5 IgM phospholipid units [MPL units] [normal value. 82 mg per deciliter [normal range. EBV. <15]. double-stranded DNA. and ribonucleoprotein. <15]). A bone marrow–biopsy specimen revealed a hypercellular marrow with maturing trilineage hematopoiesis. we determined that she needed additional treatment. This patient was treated with glucocorticoids and intravenous immune globulin (IVIG) during her hospitalization. She was readmitted to this hospital. Unfortunately.org november 21. All rights reserved. immunosuppressive agents. a monoclonal antibody to the B-cell antigen CD20. and chemotherapy (Table 4). venous thromboembolism. splenectomy was performed. For personal use only. Because of the refractory course of the disease. splenectomy.19. low-grade fevers.The n e w e ng l a n d j o u r na l of m e dic i n e Table 4.8 IgG phospholipid units [GPL units] [normal value. 2014. The usual dose of rituximab is 375 mg per square meter of bodysurface area per week for 4 weeks. Severe arthralgias and myalgias. She had elevated levels of anticardiolipin antibodies (anticardiolipin IgM antibody level. to a dose of 20 mg per day. meningococcal. we considered splenectomy. . as well as postoperative bleeding. Rituximab The patient was given rituximab after testing for HBV DNA was negative. 86 to 184].12. No other uses without permission.14. anticardiolipin IgG antibody level. 142. 2040 n engl j med 369. the tapering of prednisone was begun. the dose of prednisone was increased and another course of IVIG was administered. and positive tests for ANA (at 1:40 and 1:160 dilutions). and the overall remission rates are 20 to 40%. the initiation of second-line therapy is generally indicated. but there are several studies that show the effectiveness of IVIG in conjunction with glucocorticoids. <15]). and on rare occasions progressive multifocal leukoencephalopathy. as was testing performed as part of a rheumatologic workup. C4 level.
and bone marrow transplantation (Table 4). The ANA titer rose to 1:320. splenic sequestration of red cells and a compensatory response to peripheral destruction of blood cells. 1A) showed hypercellular marrow with normal maturing trilineage hematopoiesis. Unfortunately. <1:10). PLEASE NOTE: and hemosidFigure has been redrawn and type has been reset. Rosovsky: After splenectomy. The guideline that re- Figure 1. Pathological examination of the spleen (Fig. extramedullary hematopoiesis. recurrent evans syndrome after splenectomy A B A workup for recurrent Evans syndrome after splenectomy involves ruling out the presence of an accessory spleen and continuing to look for secondary causes.14. 69 mg per deciliter. The findings were consistent with a compensatory marrow response to cytopenias. the administration of glucocorticoids was tapered and stopped. All rights reserved. 2013 2041 The New England Journal of Medicine Downloaded from nejm. Pathological examination of a bone marrow–biopsy RETAKE with 1st specimen (Panel A) Wright shows hypercellular marrow AUTHOR ICM 2nd normal hematopoiesis.org november 21. Eli Miloslavsky (Rheumatology): When considering a diagnosis of SLE. findings consistent with splenic sequestration of red cells and a compensatory response to peripheral destruction of blood cells. 5 months later. a scan of the liver and spleen. AUTHOR. JOB: 36921 ISSUE: 11-21-13 n engl j med 369. we start with a thorough evaluation of clinical manifestations that may be attributed to SLE. azathioprine. and a viral serologic test. 2014. Options for treatment include retreatment with glucocorticoids or rituximab (if >1 year has passed since the last infusion).case records of the massachuset ts gener al hospital Dr. The rheumatology department was again consulted. high levels of β2-glycoproteins (>100 U per milliliter). immunosuppressive agents. chemotherapy. and antibodies to double-stranded DNA were elevated at a 1:20 dilution (normal value. extramedullary hematopoiesis. The vaccinations were readministered. and hemosiderin-laden macrophages. 1B and 1C) showed congestion.org on January 22. Cytogenetic analysis revealed a normal female karyotype. Platt: Pathological examination of the bone marrow–biopsy specimen (Fig. The patient continued to have high levels of anticardiolipin antibodies (anticardiolipin IgM antibody level. with no evidence of an underlying abnormality in the bone marrow. No other uses without permission.16. For personal use only. The findREG Fmaturing FIGURE trilineage 1a-c 3rd CASE ings are consistent with a compensatory marrow reTITLE Revised EMail to cytopenias. with no sponse evidence 4-C of an underlyLine SIZE ing Enon abnormality of the marrow. Copyright © 2013 Massachusetts Medical Society. . Thoughts from the Rheumatology Department C Dr. findings consistent with Please check carefully. danazol. erin-laden macrophages. 189 MPL units).H/T Pathological ARTIST: mst boneH/T 16p6 conFILL Combo B and C) shows examination of the spleen (Panels gestion. Bone Marrow–Biopsy and Splenectomy Specimens (Hematoxylin and Eosin). and low levels of complement (C3 level.21 nejm. 6 mg per deciliter). Dr. the patient had a relapse. C4 level.26-33 Repeat testing revealed persistent positive results on the direct antiglobulin test and negative results on screening for cold agglutinins.
2007. Njoku NF. Lloyd Axelrod. Cohen AS.25:1271-7. children. which have a broad differential diagnosis. in clinical practice. Arthritis Rheum 1997. which requires monitoring with periodic urinalysis. we initiated the administration of azathioprine as a glucocorticoid-sparing agent. Drug-induced immune hemolytic anemia.21 nejm. therapy. 10. although large controlled trials for the treatment of SLE manifestations unrelated to the kidney References 1. Friedberg RC.org. No other uses without permission. This patient had a low ANA titer and a moderate level of anticardiolipin IgM antibodies at symptom onset. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982. 5. 12. 7. There are reports of the efficacy of azathioprine in patients with the Evans syndrome as well as in those with SLE. the hematocrit dropped again. Klutts JS. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Initially. Am J Hematol 2002. Dhaliwal G. Hochberg MC. Fina l Di agnosis Autoimmune hemolytic anemia and thrombocytopenia (Evans syndrome) due to systemic lupus erythematosus.23:333-46. Hemolytic anemia. hypocomplementemia. et al. All rights reserved. J Clin Microbiol 2009. the relation of erythrocyte antibody production to activity of the disease. and Yi-Bin Chen for helping to organize the conference. Arch Gynecol Obstet 2005. the patient was no longer taking glucocorticoids. the diagnosis of SLE could not be made with confidence in this patient because the only manifestations were hematologic abnormalities. Copyright © 2013 Massachusetts Medical Society. Autoantibodies can be present in patients with SLE for as long as a decade before the onset of symptoms34 and can continue to develop after the onset of symptoms.11 is useful. Bhattacharjee P. with rising titers of ANA and antiphospholipid antibodies and a positive test for antibodies to double-stranded DNA. Holmes KK. Tan EM.org on January 22. Perez NR. Emergency peripartum hysterectomy in a tertiary London hospital. Genital herpes simplex virus infections: current concepts in diagnosis. It is possible that she did not have other manifestations of SLE because of the immunosuppressive agents she received throughout her illness. autoantibodies continued to develop. In consultation with Dr. Am Fam Physician 2004. 54(RR-16):1-31. 40:1725. but these criteria were created for use in clinical studies. elevated inflammatory markers. [Errata. Parker CJ.98:973-83. we increased the azathioprine to a therapeutic dose (2 to 2. Jandl JH. Duane RT. Autoimmune hemolytic anemia. and positive test for antibodies to doublestranded DNA (which is more than 95% specific for SLE in the appropriate clinical setting) made the diagnosis of SLE much more likely.56: 1267. the most notable of these is nephritis. Hemolytic anemia. Disclosure forms provided by the authors are available with the full text of this article at NEJM. No potential conflict of interest relevant to this article was reported. Corey L. Evans RS. and prevention. Bone marrow failure syndromes: paroxysmal nocturnal hemoglobinuria. Because of the elevated risk of thrombosis in patients with SLE and antiphospholipid antibodies. Hematol Oncol Clin North Am 2009. Acquired hemolytic anemia. Tierney LM Jr. Rosovsky.5 mg per kilogram per day). Kadir RA. as the prednisone dose was being tapered. We thank Drs.268:482-6. Subsequently. the rising titers of antiphospholipid antibodies. the significance of thrombocytope- 2042 n engl j med 369.69:2599-606. We increased the dose of prednisone and added hydroxychloroquine.org november 21. Selo-Ojeme DO. David Dudzinski. . 8. and adolescents.] 9. Hematology Am Soc Hematol Educ Program 2009:73-9. Izuwa- are lacking. N Engl J Med 1963. After several months. The hematocrit and platelet levels have remained normal. which has been shown to prevent flares of SLE. a patient with SLE often does not meet 4 criteria at once. This case was presented at the Medical Case Conference. 2. 47:3204-10. For personal use only. 2013 The New England Journal of Medicine Downloaded from nejm.The n e w e ng l a n d j o u r na l of m e dic i n e quires 4 of 11 criteria for the diagnosis of SLE10. Six months later. The patient's thiopurine methyltransferase genotype was normal. and a low ANA titer. 11. Ford BA. 2014. Evidence-based approach for interpretation of Epstein-Barr virus serological patterns. administration of a daily baby aspirin was begun. 6. Rosovsky: We initially administered a low dose of azathioprine (50 mg per day). MMWR Morb Mortal Wkly Rep 2006. Garratty G. MMWR Recomm Rep 2005. findings that eventually confirmed the diagnosis. Ann Intern Med 1983. Cornett PA. Gronowski AM. 3.55:158-9. Gehrs BC. as we tapered the prednisone dose. Dr. Mandakolathur Murali.69:258-71. An important aspect of treating patients with SLE is monitoring for additional disease manifestations. as the illness progressed.271:154-9. and she has continued to take azathioprine and hydroxychloroquine without any adverse events. Fries JF. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants. Hasan Bazari. 4. We recommended adding hydroxychloroquine.
et al. 21. Akpek G. Chen G. Blood 2009. 34. Evans syndrome: results of a national survey. Am J Hematol 2004. Weintraub L. Danazol in autoimmune haemolytic anaemia. Eur J Haematol 2005. Mak A. and treatment. neurologic. Am J Med 1967. The treatment of acquired hemolytic anemia with adrenocorticotrophic hormone (ACTH). and cardiac studies. Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference material is now eligible to receive a complete set of PowerPoint slides. Am J Hematol 1999. Verhoef G. Boston. Ali K.org on January 22.61:98-102. are included. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. High-dose intravenous intact IgG infusion in refractory autoimmune hemolytic anemia (Evans syndrome). et al. Dameshek W. Rituximab for refractory Evans syndrome and other immune-mediated hematologic diseases. clinical course. Br J Haematol 2002.244:11727. tables. Pignon JM. 29. autoimmune hemolytic anemia. Am J Pediatr Hematol Oncol 1988. Traynor AE. Dechartres A. Wang W. Wolf RC. Hoffbrand AV. Idiopathic acquired autoimmune hemolytic anemia: a review of forty-seven cases treated from 1955 through 1965. Chaplin H Jr. et al.349:1526-33. AMA Arch Intern Med 1951. This slide set contains all of the images from the CPC. N Engl J Med 1950.case records of the massachuset ts gener al hospital nia and leukopenia. Bussone G. Duane RT. Michel M. Every year 40 sets are produced. Shvidel L. Comparative response to splenectomy in Coombs-positive autoimmune hemolytic anemia with or without associated disease. Ribeiro E. not only those published in the Journal. Blood 1949. MA 02114 (telephone 617-726-2974) or e-mail Pathphotoslides@partners. Wang WC. 33. Anderson D. Kotb R. Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura. McAneny D. 117:712-5. Shanafelt TD. Liu C. Mathew P.43:25473. The cost of an annual subscription is $600. Stiakaki E. Emilia G. Howard J. et al. Oda H. 31. Efficacy of mycophenolate mofetil in adult refractory auto-immune cytopenias: a single center preliminary study. Bone Marrow Transplant 2001.114:316772. et al. Kalmanti M. 24. Bertesi M. and Evans syndrome. which began in January. 15. 13. may be obtained from the Lantern Slides Service.28:903-5. Primary thrombocytopenic purpura and acquired hemolytic anemia: evidence for a common etiology. Nakamura A.93:341-4. Copyright © 2013 Massachusetts Medical Society. Am J Hematol 2009.84:153-7. or individual sets may be purchased for $50 each. Honda A. No other uses without permission. Br J Haematol 1996. All rights reserved.83:343-5. 17. Takahashi K. Radiographic. Department of Pathology. and diagrams. Sugita K. J Pediatr Hematol Oncol 1997. averaging 50-60 slides per set. 78:1340-6. Nakajima H. 2013 2043 The New England Journal of Medicine Downloaded from nejm. Mycophenolate mofetil for the treatment of refractory auto-immune haemolytic anaemia and auto-immune thrombocytopenia purpura. Vincristine-loaded platelet infusion for treatment of refractory autoimmune hemolytic anemia and chronic immune thrombocytopenia: rethinking old cures. Transfus Med Rev 2007. Papadopoulos EB. McClain MT. Allgood JW. Pinganaud C. 27.4:1196213. 25. Tefferi A. Massachusetts General Hospital. Danilatou V. Each set is supplied on a compact disc and is mailed to coincide with the publication of the Case Record. J Intern Med 2009. Longo G. Miranda M. et al. Madueme HL. 32. Am J Hematol 2006. 18. 22. Guidelines on the use of intravenous immune globulin for hematologic conditions. Mantadakis E.19:433-7. Evans syndrome in childhood: pathophysiology. Prentice HG. 28.14:856-8. Oyama Y. Mayo Clin Proc 2003. Kim TH.107:744-6. Dierickx D. Long-term salvage treatment by cyclosporin in refractory autoimmune haematological disorders. Induction of remission with intravenous immunoglobulin and cyclophosphamide in steroid-resistant Evans' syndrome associated with dermatomyositis. Schwartz LI. N Engl J Med 2003. Br J Haematol 1993. Messora C.21:Suppl 1:S9S56. 16. Mycophenolate mofetil for refractory haemolytic anemia in systemic lupus erythematosus. with identifying legends. For personal use only. 19. Burt RK. Payne R. including digital images. Lupus 2005. Yoo DH. Chang DK. Mehta A.20:63-6.org.10:330-8. Shtalrid M. Trichet C. 26. Sigler E. Clin Rheumatol 2001. 14. Chanet V. Copyright © 2013 Massachusetts Medical Society.75:60-4. 20.87:48-65. Rubertone MV. as well as unpublished text slides. 23. Berrebi A. Evans RS. J Pediatr 1985.21 nejm. n engl j med 369.266: 484-91. Blanchette V. Van Hoof A. Rituximab in auto-immune haemolytic anaemia and immune thrombocytopenic purpura: a Belgian retrospective multicentric study. and photomicrographs. Rosenthal MC. 30. gross specimens.81:423-5. 2014. Dechartres A. The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases. Application forms for the current subscription year. Mok CC.org november 21. Poirson E. Arbuckle MR. Allogeneic stem cell transplantation for Evans syndrome. Efficacy and safety of rituximab in adults' warm antibody autoimmune haemolytic anemia: retrospective analysis of 27 cases. shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record.77:303-10. et al. . Rochant H.
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Visit Indonesia Fremantle Bali 2011 bittersweet win for Limit
by Bernie Kaaks on 3 May 2011
The foredeck crew acknowledge the finish team as Limit crossed the line at Bali - Visit Indonesia Fremantle Bali 2011 Trevor Milton
Limit added yet another trophy to Alan Brierty's cabinet when she claimed line honours in the Visit Indonesia Fremantle Bali 2011 international yacht race. In the process, she shattered Rolly Tasker's 30 year old record for the race, finishing in a little over six days and five hours.
Amid the celebrations however, crewman Mike Hughes spoke of the distress of losing crewman Darryl Harris following an accident on the first day of their record breaking journey.
'We spoke to the big fella by phone a little while ago,' said Hughes after they arrived. 'He broke three ribs, one of them in two places, and his lung was partially collapsed.'
The accident occurred while the boat was experiencing heavy conditions just over an hour south of Geraldton. Harris was positioned at the back corner of the boat as it tacked lost his grip when the boat tacked, throwing him across the full width of the yacht, a distance of almost 5 metres.
Harris is a big man, weighing well over 100kgs, and fell heavily across the sloping deck until his chest collided with the runner winch on the opposite side of the deck, which has flanges on its upper edge. The damage to Harris' chest was instant and painful and the crew recognized immediately that they had an emergency to deal with.
Hughes paid tribute to Dr Clews at the emergency department of Fremantle Hospital, who gave advice on the best way to treat the injury by satellite phone. Having dealt with the immediate effect of the injury and administered pain relief, the crew then transferred Harris to a pipe cot which they dismantled from inside the yacht, covered him with a sleeping bag, and painstakingly transferred him into the main cabin inside the big yacht.
In the meantime, the decision had been made to divert into Geraldton, where a waiting ambulance collected Harris for the transfer to Geraldton Regional Hospital, where he continues to make a good recovery.
Local yacht club members from Geraldton jumped to the rescue and replaced the drugs that had been used, which the Geraldton Port Authority was able to transfer to Limit, before she departed, losing about three hours in the process. Although she will not be penalized for the stopover, she will not be able to claim time under the rules of the race, making her record breaking effort even more remarkable.
The camaraderie on Limit has been remarkable too, given the disparate nature of the individuals. Some of Brierty's permanent crew combined with specialists like Ian 'Barney' Walker, a Victorian, Rod Keenan, a New Zealander and a number of well respected Western Australians. Brierty though, leads by example. On the day after the accident, after yachts had finished their radio position reports, Brierty's distinctive voice called the race control office asking for an update on Darryl Harris because 'We are all worried about him.' This sort of genuine concern for his fellow man might illustrate why Brierty has little difficulty in assembling some of the finest sailors in the world to race with him.
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Ellison, together with liberal commentators and some union leaders, demanded that Obama go to Wisconsin in support of the teachers and other public sector workers. But White House officials believe the demonstrators have made the best case on their own and point to public opinion surveys that indicated support for bargaining rights.
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"In Wisconsin, it's been a much more organic movement there," said David DiMartino, a Democratic political consultant and former Senate staffer. "The White House doesn't need to get involved."
The bipartisan criticism of Obama on Libya has less to do with low profile rhetoric — the president has been vocal in his demand that Gadhafi step down — than with the direction of the president's policy. Democratic Sen. John Kerry of Massachusetts, Republican Sen. John McCain and independent Sen. Joe Lieberman have all called for the United States to impose a no-fly zone over Libyan airspace.
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"It's also important from a political perspective to, as much as possible, maintain the strong international coalition that we have right now."
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Stealth Lawyer: Forager for Restaurant Daniel
Nov. 21 (Bloomberg) -- Ex-lawyer Tama Matsuoka Wong has a rather unusual job: she's the official forager for Daniel, the New York City restaurant of acclaimed chef Daniel Boulud. The former in-house counsel for Merrill Lynch had been gathering foodstuffs in the wild for some time when she first ate at the restaurant. She brought some of her edible plants with her, and the encounter developed into a full-time job. Wild edibles are often "more flavor dense and more nutrient dense" than farmed foods, she says. Her holiday tip: pine needles can be delicious. (Source: Bloomberg)
Most Recent Videos
CIBC's Tal: We Need to Monitor Subprime Loans in Canada
15:14 - According to the latest report from CMHC, condo building activity in Toronto appears to be "well managed," unlike the 1980s housing bubble. Yet, BOC Governor Stephen Poloz recently addressed the pace of rising home prices in Canada's two hottest markets - Toronto and Vancouver. Benjamin Tal, deputy chief economist at CIBC World Markets, joins Bloomberg TV Canada's Amanda Lang to discuss the current state of the Canadian housing market, where it's headed and what measures need to be taken to "cool" foreign buyers. (Source: Bloomberg)


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Don't feel bad, some girls just turn into bigfoot naturally.
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Copyright ©2016 Rich "Lowtax" Kyanka & Something Awful LLC.


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Stillspotting nyc
In collaboration with architectural firm Snøhetta, legendary composer Arvo Pärt recently curated a series of stillspots around Lower Manhattan – a small number of in- and outdoor spaces (like the one pictured) that explore the special relationship between space and sound. The project was completed as part of the Guggenheim's Stillspotting nyc initiative, a two-year experiment that aims to locate, celebrate and emphasise – via art projects, an insightful user-generated noise map, and weirdly intriguing video data – the importance of quiet amidst one of the loudest cities in the world.
- The creative team behind John Grant's post-apocalyptic world
- They have beauty, they have grace, they are Jack Mears' ceramic dogs
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- Illustrator Jan Robert Duennweller's erratic style creates "visual headlines"
- Réka Neszmélyi's boundary breaking identity for Hungarian Bánkitó Cultural & Music Festival 2016
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According to Tremont Electric, Hurricane Sandy's path over Lake Erie brought back memories of one of the worst pro sports stadiums ever constructed. Strewn alongside the shores of the Bratenahl section of Cleveland this morning were pieces of the infamous Cleveland Municipal Stadium that was destroyed in November 1996. The debris was used to make three man-made reefs in Lake Erie — though I'm not totally convinced that that's not a euphemism for throwing your trash in the lake — and Sandy unmade them.
2. Cleveland Municipal Stadium in 1991:
3. Cleveland Municipal Stadium this morning:
No word if the most disgusting urinal troughs the world has ever seen have reared their ugly heads. No one has reported any mutations yet so I'm thinking we're still safe on that front.
- DNC Day 3: President Obama dropped the mic with "Don't boo, vote," and vice presidential nominee Tim Kaine reminded people of their dads 👴
- Prosecutors have dropped remaining charges against Baltimore police officers related to the death of Freddie Gray.
- Twelve states will support Obama's transgender policies in court after other states sued to block the rules.


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Le Meridien N'fis
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Le Méridien N'Fis is nestled in five and a half hectares of lush parkland in the Menara district of the city. Guests can enjoy views of the mountains, garden, park or swimming pool from the rooms and suites.Once twilight falls, the enchanting spectacle of the illuminated Andalusian gardens, complete with tinkling fountains and coconut trees silhouetted against the dusk, is an unrivalled sight of scenic beauty.Le Méridien N'Fis offers three world-class restaurants, and spectacular spa facilities. Two of the finest golf courses in Morocco are located near the hotel. ...read more
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New York, NYUSA
February 28, 2013
No answer yet
Web devleoper
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I am not running the IIS. I am working on ASP.NET development server. I created asp.net website using File system and I created simple ASP.NET web service that is Dollar Converter. While adding Web Reference , the error occurred that is
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|Sent on:
|Wednesday, January 2, 2013 7:52 AM
Dawn was right on in pointing out the publicity backing we need in order to help stem the flow of exotic animal breeding. And, along those lines, The Wildcat Sanctuary has created several moving Public Service Announcements along with a radio PSA and collateral print/media ads that you can watch and share from this link: http://www.wildcatsanctuary.org/no-more-wild-pets-campaign/
I hope everyone will take just a moment to watch how they incorporated the lions, tigers, and cougars they've ended up rescuing into these poignant pieces. You can watch them on YouTube at: http://youtu.be/iL8LNy6up9Q and http://youtu.be/TabW3mTZ5xY and http://youtu.be/ufm8gdtCjN0
Dawn, would you be able to share these with your network? We're trying to get as much national coverage as possible since the Minnesota market has already been airing these spots. If anyone else there has some resources or groups they could share these with, please let me know.
As a group, we can accomplish some pretty spectacular things!
They will never know freedom.
Can they at least know compassion?
From: [address removed] [mailto:[address removed]] On Behalf Of Dawn Marie Groth
Sent: Tuesday, January 01,[masked]:59 PM
To: [address removed]
Subject: Re: [AnimalACTionNetwork] A letter of inspiration for 2013
This is an excellent article.... and as someone who was there in the 70's to see that native american man with a tear in his eye.... and help clean up the streets... I know there was a national campaign. widely publicized. Commercials, signs posted everywhere, and it even got into the schools, which was how I got involved. Our class went on an outing for clean up earth day. With that much publicity, it is not surprising that we actually accomplished this.
To have such a campaign for animals.... we would need that much involvement. That much publicity. That many people saying, "Hey, this really isn't right, lets help fix it" If a campaign were to be created with a short title. And we could get enough groups to back it nationally... we might be able to actually kick off a widely publicized campaign. That is what the animals need.
Dawn Groth
From: Julie
Sent: Tuesday, January 01,[masked]:08 AM
To: [address removed]
Subject: [AnimalACTionNetwork] A letter of inspiration for 2013
The Sanctuary I volunteer for published a letter today I thought was very inspirational for all of us in the trenches, working so hard to do everything we can to assure all animals are treated humanely. I wanted to share it with you as we head into the new year:
The Wildcat Sanctuary's director has a quote that often rings in my head. "We cannot rescue ourselves out of the captive wildlife crisis." I've only been at the Sanctuary a short time and I humbly admit now that when I started here I thought we COULD rescue our way out. I thought if we and other accredited sanctuaries just took in all the unwanted, exploited abandoned cats, we could "fix" the problem.
Now, six months later and countless desperate phone calls from people wanting to surrender cats or report abuse, I know the truth. We cannot rescue our way out of the captive wildlife crisis. For every cat we rescue, a breeder somewhere is making six more. For every exotic pet we have surrendered to us, there are hundreds more left in tiny cages, chained to the ground or ignored in backyards.
While this information came as a huge disappointment to me, and a stunning reality check that has kept me awake on more than one night, it has also inspired me to learn more about how we CAN make a difference.
I often think back to the 1970′s impactful public service announcement showcasing a Native American man in a canoeshedding a tear for the environment. Back in the 70′s, it was commonplace for people to throw trash out their car windows. Fast food bags, pop cans, empty cigarette packs and even diapers were tossed with no regard for what it may be doing to the environment.
Through the years, we realized the error of our ways. We woke up to our ignorance of the truth. If everyone uses the earth as their garbage can, there will no future for our children. I don't think the people of the 70′s and before were any meaner, or less intelligent than we are today. They were just ignorant, uninformed and not educated on the environment.
Likewise, I think this is the very root of the captive wildlife crisis. People do not realize that when they attend circuses or pet a tiger at a roadside zoo they are greasing the palms of the people whose greed has led to the problem of homeless and abandoned exotic pets in the first place.
If people continue to buy these "pets" from breeders instead of adopting one of the millions of appropriate pets from a shelter, they will continue to perpetuate the problem. I don't believe the general public would condone or celebrate the captive, exploited existence of so many of these animals – they just don't realize how they contribute.
If, every day, those of us who speak for the animals touch one person and ask them to touch another and so on, be it in conversation or through Facebook or in other creative ways, we can make a difference.
Just as our children now know that they can't throw their garbage out the window, I trust that one day their children would not think of not spaying or neutering their pets or going to a circus or petting a baby tiger at the mall or getting a serval as a pet.
Just like the Native American man who shed a tear for the environment, I like to believe that every tear we shed today will spare a tear for future generations. I know that we can't rescue our way out of the exotic animal pet trade. But we can educate our way out. As we begin 2013, please join us in continuing to spread the No More Wild Pets message.
Together, we can change the future!
Holly Henry – The Wildcat Sanctuary, Communications Manager
Please Note: If you hit "REPLY", your message will be sent to everyone on this mailing list ([address removed])
This message was sent by Julie ([address removed]) from "Animal ACTion Network" Colorado.
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Set my mailing list to email me As they are sent | In one daily email | Don't send me mailing list messages
Meetup, PO Box 4668 #37895 New York, New York[masked] | [address removed]
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Definition of prostyles
plural of prostyle 1
The word "prostyles" uses 9 letters: E L O P R S S T Y.
No direct anagrams for prostyles found in this word list.
Words formed by adding one letter before or after prostyles (in bold), or to eloprssty in any order:
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MarriageRuntime: 10 Min. - UnabridgedFREEFREEPastor James MacDonald offers 10 practical principles to make Christian marriages great.Learn More
Breaking Every ChainRuntime: 9 Min. - UnabridgedFREEFREEPastor James MacDonald explains practical steps Christians can apply to break free from fear.Learn More
The Numbers of HopeAuthor: Max LucadoRuntime: 6.5 Min. - UnabridgedFREEFREEBased on the book 3:16, best-selling author Max Lucado reveals the concept of God's love as shown in John 3:16.Learn More
The Certainty of SalvationRuntime: 10 Min. - UnabridgedFREEFREEPastor James MacDonald addresses some common questions about having assurance of our salvation.Learn More
Hope for Hard TimesRuntime: 5 Min. - UnabridgedFREEFREEIn hard times, it is easy to feel as if there is no hope. But Christ's work on the cross gives reason for hope even in the darkest of times.Learn More
How Can We Know That We'll Go to Heaven?Author: Randy AlcornRuntime: 7 Min. - UnabridgedFREEFREEFor every American polled who thinks they are going to hell, there are 120 who think they're going to heaven. Author Randy Alcorn explains that heaven isn't our "default destination" and that specific preparation must be made if we are to safely arrive in heaven.Learn More
Building a Home God's WayRuntime: 9 Min - UnabridgedFREEFREEPastor James MacDonald illustrates the importance of building a family God's way--with Christ as the center.Learn More
In Our PlaceAuthor: Mark DriscollRuntime: 7 Min. - UnabridgedFREEFREETaken from the book Doctrine, this tract focuses on why Christ's death on the cross for our sins, as our substitute, was necessary in order for us to have the opportunity to be reconciled with God.Learn More
Good News Tracts Collection
Crossway Good News TractsAuthor: Various AuthorsFREEFREEThis collection includes audio MP3 and PDF files for 27 Crossway Good News Tracts. (Due to the large number of files, this product is only available as a ZIP file.)Learn More
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3 bedroom houses to rent in Broxbourne
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3 bed end terrace house to rentSilverfields, Broxbourne EN10
Available immediately
Currently undergoing an overhaul and redecoration. Extended 3 bedroom end of terrace property. Good size kitchen, large lounge. First floor bathroom. Ground floor WC. Garage and Ample parking, Sorry, no DSS, pets or smokers.
Note: Distances are straight line measurements
- Broxbourne (0.8 miles)
- Cheshunt (2.4 miles)
Latest Broxbourne 3 bedroom houses to rent
Zoopla is one of the UK's leading property portals, helping you to find property for sale and to rent and make smarter decisions when buying and renting homes in the UK. Discover information on homes in Broxbourne by researching Broxbourne property values, Broxbourne house prices paid, our Broxbourne property market overview and find Broxbourne agents.


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List of sober homes rooms
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text:
St Edward's
St Edward's School and St Edward's Preparatory School welcome pupils from 1 - 18 years. Situated on two sites, approximately five minutes from each other, and enjoying over 45 acres of wonderful grounds, both Schools share a commitment to excellence in academic study and the provision of outstanding pastoral care.
The strong Christian values of St Edward's provide the framework around which we enrich the lives of each and every pupil and member of our wider community. We prepare pupils to lead fulfilling and purposeful lives which will contribute to the wider world in which we live. St Edward's pupils leave both Schools fully prepared for the road ahead, be that a successful transition to Senior School, or the move to university and beyond. Parents comment on the positive ethos and values of St Edward's and our pupils are high achievers, happy, respectful, articulate, caring and responsible young people who are well-grounded..
Publications and Social Media
For the latest news, stories and features about St Edward's School, read our weekly news bulletins (Prep WeekEnd and The WeekEnd) or check out our Youtube channel, Issuu account and Facebook page.
Saturday 24th September 2016
Prep School Enrichment Morning 9am - 12 noon
Senior School Open Day 9am - 3pm
Prep News
Prosecco and Canapés Evening 2016
Book your place now!
23 June 2016
Her Majesty's 90th Birthday
A special guest visits
10 June 2016
Senior News
St Edward's School - Sports Day 2016
On YouTube now
08 July 2016
4-2-11 Summer Camp
25th July - 18th August
07 July 2016
Prep Calendar
Senior Calendar
- Summer Holiday


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Lorraine Gregory Corp
Direct Phone: (631) ***-****
Email: g***@***.com
110 Schmitt Boulevard
Farmingdale, New York 11735
United States
Over the years, the growth of the Lorraine Gregory Group has required physical expansion on five occasions - first from its 1,000 sq. ft. storefront to 3,000 sq. ft., then to 6,000, then to 13,000, and the last move in January 2001 to the current 15,000 s... more
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LI Community Foundation
Board Member
Business Advisory Committee of AHRC Suffolk
Member, Board
Advisory Board
Dolan Family Health Center of Huntington Hospital
Farmingdale Chamber of Commerce - Search Results
www.farmingdalenychamber.org [cached]
www.farmingdalenychamber.org [cached]
LGC Named FUTURE 50 Award Recipient | Company Newsroom of Lorraine Gregory Communications
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Farmingdale Chamber of Commerce - Search Results
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Anthony Demetriou
Current Foundation
James Demetriou
Saint Sophia Cathedral
Demetris Demetriou
University of Leeds
Dem Demetriou
Thomas Demetriou
Enterprise Monkey


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The joy of Eid"The first thing I do on Eid morning is to visit the Sufi Dargah in Mahim where I feed the poor and homeless. After a round of 'namaaz', I return home to break the fast with my family. The breakfast is usually 'Mutton ... Deccan Herald, 2 weeks ago
3 images for "Mahim Dargah"
Mumbai weekend calendar: July 15 to 17
To continue reading, we request you to support us by disabling your Ad Blocker In order to serve content on our website, we rely on advertising revenue which helps us to ensure that we continue to serve high quality unbiased journalism. To know ...Hindustan Times, 1 week ago
Mumbai Development plan: Errors galore even in revised DP
Mumbai: The Mumbai Development plan (DP) 2034 is once again riddled with thousands of glaring errors and these mistakes have been pointed out by the citizens across the city. Advocate Godfrey Pimenta from Watchdog Foundation has alleged that, The ...The Freepress Journal, 2 weeks ago
Half-built Dharavi skywalk shatters traffic-ease hope
Meant to ease up traffic in the busy T-junction of 60 Feet Rd, the half-finished skywalk has only added to the nuisance. A half-built skywalk, initially intended for being built between Dharavi's Abhyuday Bank Chowk and Mahim (east) for easing ...Mumbai Mirror, 2 weeks ago
Eid-ul-Fitr celebrated in country with traditional gaiety, fervour
New Delhi, Jul 7: Eid-ul-Fitr, marking the conclusion of the holy month of Ramzan, was today celebrate across the country with traditional gaiety and fervour. Devotees assembled at various congregation sites in their respective towns and villages to ...Newshence.com, 2 weeks ago
News flash: Bihar CM Nitish Kumar extends Eid greetings
Bengaluru, July 7: PM Narendra Modi began his 4-nation tour to Mozambique , South Africa, Tanzania and Kenya. Modi arrived in Mozambique today. Get all the latest news updates of the day: 1.51 pm: Bihar CM Nitish Kumar extends Eid greetings ...Oneindia, 2 weeks ago
Heavy showers jam traffic, Mumbaikars can expect wet Sunday
Mumbai: The spell of heavy rainfall that began on Friday continued to lash the city and its surrounding areas on Saturday and threw traffic out of gear. The India Meteorological Department (IMD) has forecast that the heavy downpour will continue for ...Times of India, 1 month ago
HC to study Sabarimala case before Haji Ali verdict
By Vinay Dalvi | Posted 2 hours The High Court Bench is likely to announce the verdict on June 28 The Bombay High Court yesterday said it would pronounce judgment in the case of women's entry in Haji Ali Dargah on June 28. The court also ...Mid Day, 1 month ago
On the iftar trail
As we enter the month of Ramzan, we sniff out the best iftar treats around town, with a little help from city chefs Ramzan is a special time of the year for foodies in Mumbai. Iftar parties and iftar special delicacies line up on streets around the city, ...Asian Age, 1 month ago
Cemetery as homeless shelter: dark humour from urban surveyors
Last week, when members of a Poinsur church found that the city's revised Development Plan (DP) had marked their parish graveyard as a shelter for homeless people, they wondered whether it was a dreadful attempt at dark humour by bored surveyors. ...Hindustan Times, 1 month ago
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(from TopCare)
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