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Two subscribers to the ASH Practice Update also contribute to the high cost of medical care buy estrace 2mg with visa. A total of 154 suggestions were received order estrace 2 mg overnight delivery, particularly salient to the field of hematology because hematology is representing 81 unique items generic 2mg estrace fast delivery. Four items overlapped substantially a laboratory-based specialty dependent on a wide array of blood- with recommendations from other professional societies in previous and tissue-based tests and because the cost of contemporary hematology/oncology treatments is rapidly escalating estrace 1 mg without prescription. One overlap item was retained due to a slightly different focus than its predecessor and because the ASH ASH has identified 5 hematologic tests and treatments that should CWTF felt that this item (regarding RBC transfusion) was central to be questioned in the circumstances indicated (Table 3). These 5 items were selected using a rigorous and reproducible methodology hematology practice. The initial short list of 10 items is listed in that sought input from an array of ASH committee members and Table 4 in Appendix 1B. The methodology we developed could be adapted to future In May 2013, 5 ASH Choosing Wisely items and one alternate Choosing Wisely campaigns or similar initiatives. Minor language changes were recommended by the ABIM Foundation and were endorsed by ASH’s first recommendation advises against liberal transfusion of the ASH CWTF. Transfusion of the smallest effective dose of RBCs is item involving diagnostic testing for lymphoma be removed in favor recommended because, compared with restrictive strategies, liberal of a recommendation regarding surveillance computed tomography 10-14 transfusion does not improve patient outcomes. Therefore, (CT) scans in aggressive non-Hodgkin lymphoma (NHL) due to a liberal transfusion generates costs and exposes patients to potential concern that the diagnostic recommendation focused more on harms from transfusion without likelihood of benefit. Consistent appropriateness of testing than on overuse of testing. The final ASH with this recommendation, we further advise that clinicians avoid CW items, including the deferred item, are listed in Table 3. Table 3 summarizes the key references supporting each of the ASH Choosing Wisely recommendations. Four of the 5 final recommen- ASH’s second recommendation advises against thrombophilia test- dations were supported by recently published, evidence-based ing in adult patients diagnosed with venous thromboembolism guidelines. One item (item #5) was supported by guidelines that (VTE) in the context of a major transient VTE risk factor such as were not clearly evidence based,5,6 so for this item, our systematic surgery, trauma, or prolonged immobility. Final ASH Choosing Wisely recommendations Key references Recommendations 1. In situations where transfusion of RBCs is necessary, transfuse the minimum number of units required to relieve symptoms 11,12 of anemia or to return the patient to a safe hemoglobin range (7-8 g/dL in stable, noncardiac in-patients) 2. Do not test for thrombophilia in adult patients with venous thromboembolism occurring in the setting of major transient risk 15,16 factors (surgery, trauma, or prolonged immobility) 3. Do not use inferior vena cava filters routinely in patients with acute venous thromboembolism 17,21-23 4. Do not administer plasma or prothrombin complex concentrates for nonemergent reversal of vitamin K antagonists (ie, 27,28 outside of the setting of major bleeding, intracranial hemorrhage, or anticipated emergent surgery) 5. Limit surveillance CT scans in asymptomatic patients after curative-intent treatment for aggressive lymphoma 5, 6, 31, 33, 34 Deferred recommendation 6. Do not diagnose or initiate treatment of lymphoma on the basis of tissue obtained exclusively with fine needle aspiration 6, 41 Hematology 2013 11 treatment. One caveat to the above recommendation involves patients who Even when relapses were detected earlier on a routine scans, there experience VTE in the setting of a major transient risk factor but was no evidence of a survival benefit with more liberal surveillance who have additional risk factors such as a positive family history or strategies. ASH recommends that CT scans are associated with a measurable lifetime risk of second- such patients seek guidance from an expert in VTE. There is a paucity of evidence supporting the use of IVC 5-year cumulative probability of lymphoma death. Filters placed for Conclusion In summary, the ASH Choosing Wisely campaign has identified 5 primary prophylaxis of PE in patients who do not have acute deep vein thrombosis of the leg are widely used24; however, there is no tests and treatments that increase the cost of medical care and evidence to support their utility and there is clear evidence that such expose patients to potential risks with a low likelihood of benefit filters cause harm. In some cases, such as the undergoing bariatric surgery, prophylactic IVC filters did not reduce recommendation against liberal transfusion of RBCs, there is a postoperative VTE, but did appear to increase the risk of death strong evidentiary basis for the recommendation. ASH recommends that retriev- of potential harms and cost. In all cases, the recommendations are able filters be removed as soon as the risk for PE has resolved and/or bounded by the current state of the science. As the evidence evolves, when anticoagulation can be safely resumed. Recent reports suggest it is possible that certain recommendations will need to be revisited. Although clearly outside of the scope of the present article, efforts are under way to ASH’s fourth recommendation advises against the use of plasma or develop quality metrics and toolkits based on Choosing Wisely prothrombin complex concentrates to reverse vitamin K antagonists items. If Choosing Wisely is successful, it may be possible in some (VKAs) in the absence of bleeding, emergent surgery, or emergent instances to demonstrate changes in practice through time trends in invasive procedures. The use of plasma or prothrombin complex large, population-based datasets. In other cases, the main positive concentrates to nonemergently reverse VKAs increases costs and outcome of Choosing Wisely may be to stimulate research in areas exposes patients to potential harm from transfusion with little singled out by Choosing Wisely as lacking a sufficient evidentiary likelihood of benefit. For the time being, we encourage physicians to consider the guidance on the optimal approach to the reversal of VKAs. For nonbleeding patients with an INR greater than 10, there are no randomized controlled trials to guide practice. A small prospective Acknowledgments cohort study suggests that most of these patients can be safely This work was supported by ASH. Suzanne Leous (ASH staff) managed by administering small doses of vitamin K rather than with provided administrative and organizational assistance to the project. ASH’s fifth and final recommendation advises clinicians to limit the Solberg. All members of the task force contributed to study design use of surveillance CT scans in asymptomatic patients in complete and implementation; L. In addition to their cost, CT scans systematic reviews; L. Hicks wrote the first draft of the manu- deliver modest doses of radiation to patients and are associated with script; M. Crowther wrote sections of the manuscript; and all a small increased risk of malignancy over the long term. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th Ed. American College of Chest Physicians Correspondence Evidence-Based Clinical Practice Guidelines. Hicks, 30 Bond St, Rm 2-084 Donnelly Wing, Toronto, ON, 141(2 Suppl):e419S-494S. M5B 1W8, Canada; Phone: 416-864-5632; Fax: 416-865-3055; 18. American College of Chest References Physicians Evidence-Based Clinical Practice Guidelines. Miyakis S, Karamanof G, Liontos M, Mountokalakis TD. Factors contributing to inappropriate ordering of tests in an 19. Influence of thrombo- academic medical department and the effect of an educational philia on risk of recurrent venous thromboembolism while on feedback strategy. Indications, complications, cost: the path to continuously learning health care in America. Billi JE, Duran-Arenas L, Wise CG, Bernard AM, McQuillan center. The effects of a low-cost intervention program on 21. Dupras D BJ, Felty C, et al; Institute for Clinical Systems hospital costs. Accessed January lymphoma: ESMO Clinical Practice Guidelines for diagnosis, 13, 2013. Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. Tangka FK, Trogdon JG, Richardson LC, Howard D, Sabatino 24. Cancer treatment cost in the United States: use of inferior vena cava filters. The price of drugs for of inferior vena cava filters and outcomes after gastric bypass chronic myeloid leukemia (CML) is a reflection of the unsustain- surgery.

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A study in 1984 of 300 women in Sierra • Type I: excision of the prepuce (a retractable Leone found that of the 90% who were circum- piece of skin covering part of the clitoris) order genuine estrace, with cised the reasons cited were tradition (85 discount estrace master card. Leone woman who practices FGM in a village 276 Female Genital Mutilation (a) (c) (b) (d) Figure 2 Different types of female genital mutilation (FGM) order generic estrace pills. ISBN: 2–913326–49–8 explains ‘If the women of our village stop this prac- Acute complications tice safe estrace 1mg, life will be meaningless to us all. It is our cul- These may include the immediate ones such as ture, and nobody has the right to take it away from shock due to pain, infection or severe hemor- us’. Acute infection with tetanus and general- WHO has taken a stand against genital mutila- ized septicemia is a frequent problem due to tion but has acknowledged that in the African the conditions in which FGM is carried out. The mortality rate of sition from both men and women and an insistence girls as a result of bleeding after FGM is unknown that westerners should not interfere with the cul- because these deaths are rarely reported to the tural practices of another nation. HEALTH COMPLICATIONS Health complications of FGM for women and Chronic complications children are serious, many and varied. They are acute or These include chronic urinary retention, obstruc- chronic. There is a broad range of complications tion to menstrual flow and consequences of infec- due to genital mutilation which women can suffer tion can lead to the following frequent occurring from during their entire life: complications: 277 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS • Chronic urinary tract infections (UTI). Full sexual intercourse may take some weeks to achieve. The presenting part can compress the bladder and the rectum due to the fetus being retained in the vagina Figure 3 Excessive keloid after female genital mutila- through infibulation itself or scar tissue of tion. If the situation lasts for many hours, tissue necrosis of bladder and rectum will develop which will lead to a vesico- vaginal (VVF) or recto-vaginal fistula (RVF) once the necrotic tissue falls off (for more information about fistula see Chapter 21). In most cases the fetus will die (Figure 5) and the mother, if she survives may suffer from serious injuries (Figure 6) and become a social outcast due to the permanent stench of urine. FGM and the resulting scar tissue causes rigidity of vaginal tissue. At childbirth the level of elasticity of the vagina cannot be expected to be normal due to scarring. In the absence of surgical interventions severe tears of the vaginal wall Figure 4 Obstructed labor due to female genital or perineum can arise with the risk of major mutilation. Dyspareunia (pain during intercourse) and trauma can lead to vaginismus and other sexual problems. One can as- sume that these problems have a high incidence among women suffering from FGM but there are hardly any statistics or studies available on this issue. In addition many victims are Figure 5 Stillborn baby due to obstructed labor caused not even aware of the fact that their symptoms by female genital mutilation. Source: Touré are related to FGM as the procedure is con- sidered as normal in their setting and they Less common complications can’t compare their health problems with some- one who has not undergone FGM. Many • Abscesses: collection of pus in wound cavities women or girls can’t express their pain and suffer after excision. Source: Touré • Clitoral neurinoma: nerve endings in the clito- ris, can be caught in the scar tissue, causing ex- cruciating pain on the slightest touch (Figure 8). A normal gynecological examination is 279 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS not possible for anatomical reasons or due to the recurrent psychological trauma of pain. As a conse- quence, screening for cervical cancer with cytology swab or direct visual inspection is extremely diffi- cult or not possible at all. The same accounts for the insertion of an intrauterine device (IUD). If you need to do a gynecological examination on an FGM victim you should consider her psy- chological and physical trauma. Explain well what you plan to do and discuss the possibility of pain relief, e. If a speculum examination is necessary use the smallest valve you have and lubricate it Figure 10 Occlusion of the introitus after female genital well. If the procedure is intolerable for your patient mutilation. If you are working in a high- incidence area of FGM it might be worthwhile to invest in pediatric specula and a vaginoscope as described in Chapter 24 and in lignocaine cream or jelly. In cases where a vaginal examination is impossible a rectal examination can be performed but it is very important to discuss this with the patient first. You should always discuss defibulation with the patient. HIV transmission and female genital mutilation The practice of FGM involves the use of one in- strument for multiple operations under non-sterile conditions and thus carries a high risk of trans- mission of infection including HIV for the women or girls undergoing FGM but as well for the circumcisor. Recently, there has been a growing interest in the relationship between the practice of female circumcision and the spread of AIDS. POSSIBLE SURGICAL INTERVENTION TO REVERSE FEMALE GENITAL MUTILATION Defibulation Figure 11 Injection of local anesthetic in the scar. Abdul Cader This is a surgical procedure to reverse infibulation by opening the vaginal introitus, uncovering the 3. Identify the midline of infibulation by lifting it urinary meatus and rebuilding, as much as possible, up using a dissecting forceps introduced in the a ‘normal’ anatomy of the external genitals. This vaginal opening and let it slide further under the procedure is especially necessary in patients with scar bridge of the infibulation (Figure 12). The operation is cases where the vaginal opening is not too nar- described step by step below: row you can use your index finger. Careful preoperative disinfection of the peri- to protect the underlying structure (urethra) neal and genital zone with iodate solution. Cut beginning from the bottom upwards several points of the scar (see Figure 11 ). Stop almost 1–2cm above the 280 Female Genital Mutilation urethral orifice. Widen the edge of defibulation daily using symmetry of the incision. Suture the single edge of the incision with welding of incision. Counsel the patient to urinate into a bowl (Monocryl 00) as shown in Figure 13. Restoration of the clitoris The French urologist Dr Pièrre Foldes is the only surgeon who has developed a surgical technique to restore the clitoris5. Place the patient under general anesthesia in lithotomy position. Open the scar on top of the clitoris stump stay- ing closely to the stump, proceeding upwards to include the residual shaft of the clitoris (Figure 14). Remove the scar tissue surrounding the shaft of the clitoris and the suspensory ligament (Figure 15). Mobilize the suspensory ligament by transect- ing it vertically (Figure 16). Fix the neo-clitoral shaft using single stitches with Monocryl on the lateral and inferior border of the shaft (Figure 17). Adapt the skin with interrupted stitches using Monocryl (Figure 17). Figure 12 Incising the infibulated vulva in the midline. Tissue is then removed from the thighs to Source: A. The surgery takes less than an hour in experienced hands and can be done as an outpatient procedure with 1 day in hospital postoperatively. Post-surgery pain may last 2 weeks and 4–6 weeks later, women claim to have a new healthy sexuality and to feel again their clitoris (Figure 18). A study found a positive change in sexual arousal in 75% of the 453 patients6. It is difficult to compare pre- and postoperative results as most patients never experienced a nor- mally functioning clitoris before their operation but patients’ satisfaction with the method could be assessed by using psychometric questionnaires. PREVENTION There are four groups of people who need to be Figure 13 Closing the defibulation. Abdul informed about the consequences of FGM in order Cader to prevent its continuation7: 281 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS (a) (b) Figure 15 Mobilizing the shaft of the clitoris. Ground actors are a cornerstone in the abolition of FGM.

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Treatment/prophylaxis of cryptosporidiosis (daily doses) Acute therapy Symptomatic Loperamide + Loperamide 1 cap buy estrace 2mg overnight delivery. The importance of good hygiene and not drinking tap water should be emphasized to patients discount estrace 1mg online, at least in countries with limited access to clean order estrace american express, adequate drinking water generic 2mg estrace with mastercard. Contact with human and animal feces should be avoided. The tendency for patients to become ill during the summer months can often be linked to swimming in rivers or lakes. In hospitals and other medical facilities, the usual hygienic measures, such as wearing gloves, are adequate. However, they should not be put in the same room with other significantly immunocompromised patients. References Abubakar I, Aliyu SH, Arumugam C, Usman NK, Hunter PR. Treatment of cryptosporidiosis in immunocompro- mised individuals: systematic review and meta-analysis. Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial. High dose prolonged treatment with nitazoxanide is not effective for cryp- tosporidiosis in HIV positive Zambian children: a randomised controlled trial. Treatment of HIV-1 associated microsporidiosis and cryp- tosporidiosis with combination antiretroviral therapy. Factors related to symptomatic infection and survival. Resolution of severe cryptosporidial diarrhea with rifaximin in patients with AIDS. Paromomycin: No more effective than placebo for treatment of cryp- tosporidiosis in patients with advanced HIV infection. Possible effectiveness of clarithromycin and rifabutin for cryp- tosporidiosis chemoprophylaxis in HIV disease. Eradication of cryptosporidia and microsporidia following suc- cessful antiretroviral therapy. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective ran- domized, double-blind, placebo-controlled study of Nitazoxanide. Smith NH, Cron S, Valdez LM, Chappell CL, White AC Jr. Combination drug therapy for cryptosporidiosis in AIDS. In the US and especially in Southeast Asia, cryptococcosis occurs much more frequently and is considerably one of the more prominent AIDS-defining illnesses worldwide. Presumably transmitted via inhalation, bird droppings are a key reser- voir for C. This pulmonary infection may remain subclinical in immuno- competent patients, but is almost always followed by disseminated disease in HIV+ patients. Apart from the lungs, the main manifestation after hematogenic spread is in the CNS. For this reason, a CSF examination is obligatory in every suspected case. However, isolated skin manifestations and lymphadenitis can also occur. Organ involvement, such as in the urogenital or gastrointestinal tract, is rare. Cryptococcosis almost always occurs with severe immunodeficiency. In a collection of 114 cases, 87% had less than 100 CD4 T cells/µl; the median CD4 count was 30 (Weitzel 1999). Many cases seen today occur in the setting of an immune reconsti- tution inflammatory syndrome. Treatment is lengthy, complicated and should be managed only on an inpatient basis. Relapses were frequent in the pre-HAART era and occurred in at least 15% of cases. In addition, cryptococcosis occurs relatively frequently in the presence of an immune reconsti- tution inflammatory syndrome. In one study from France, the mortality rate per 100 person-years was 15 in 1996– 2000, compared with 64 in the pre-HAART era although early mortality did not differ between the two periods (Lortholary 2006). Signs and symptoms The CNS manifestation with encephalitis is the most frequent manifestation (ca. Patients complain mainly of headaches, fever and confusion or clouding of consciousness which progresses rapidly over a few days. Disorders of gait, hearing, and vision may occur, as well as paresis, particularly of the cranial nerves. In such cases intracranial pressure is almost always increased. In the course of an immune reconstitution syndrome, clinical symptoms are often atypical and characterized by extensive abscesses (Manfredi 1999). Pulmonary disease leads to symptoms of atypical pneumonia with unproductive cough and chest pain. Skin lesions can initially resemble molluscum contagiosum, and later become confluent in the form of larger, ulcerative lesions. Diagnosis Cryptococcosis is life-threatening, and the mortality rate in larger studies is between 6 and 25% (Saag 2000). Rapid examination of the lungs (HRCT) and CNS in particular (MRI) should be initiated in every suspected case (e. The chest x-ray usually does not reveal much; therefore, an HRCT scan must be per- formed if pulmonary involvement is suspected. The spectrum of morphology on the image is very variable. Diffuse, small lesions similar to tuberculosis may occur, but there can also be sharply defined infiltrates reminiscent of bronchopneumonia. Every attempt should therefore be made to clearly identify the causative organism by BAL. An MRI scan of the head should always be performed if there are neurological symp- toms. However, in contrast to toxoplasmosis and primary CNS lymphoma, it usually Opportunistic Infections (OIs) 387 does not reveal much, and isolated or multiple mass lesions (cryptococcomas) are very rare. Nevertheless, intracranial pressure is often increased and a fundoscopy (papillary edema) should be performed. The most important test for cryptococcosis is lumbar puncture after a fundoscopy and/or an MRI. Diagnosis can be made via India ink stain in almost all cases. CSF must be examined even in cases with pulmonary or other manifestations to exclude CNS involvement. Cryptococcal antigen (CrAg) in the blood (titer >1:8) is a good parameter and should always be determined, especially in patients with low CD4 T cell counts (Jarvis 2011). With cutaneous involvement, the diagnosis is usually made from a biopsy. Treatment In cases of CNS involvement an immediate combination of antimycotics is urgently recommended followed by maintenance therapy with fluconazole (Saag 2000). Fluconazole alone is not sufficient, even in high doses, as shown by two random- ized trials from Africa. In these trials, mortality of cryptococcal meningitis was unacceptably high. Within the first weeks, 54–59% of the patients died (Longley 2008, Makadzange 2009). Combination prevents resistance and allows reduction of acute therapy to 4-6 weeks.

Appropri- discordant order 1 mg estrace otc, the predictive values are too low to act on and biopsy ate assessment of HIV as a comorbid condition is essential to 386 American Society of Hematology optimizing therapeutic strategies buy estrace 2 mg visa. El-Sadr WM order generic estrace, Lundgren J order generic estrace on line, Neaton JD, et al; Strategies for enced the epidemiology of hematologic cancers in HIV, and those Management of Antiretroviral Therapy (SMART) Study Group. Pooled of malignancy and the specific therapy being administered. Off-label drug use: azidothymidine and ganciclo- 14. Rituximab plus vir for treatment of Kaposi sarcoma-associated herpes virus– concurrent infusional EPOCH chemotherapy is highly effective associated MCD. Relationship of Richard Little, National Cancer Institute, National Institutes of p53, bcl-2, and tumor proliferation to clinical drug resistance in Health, 31 Center Drive, MSC 2062, Bldg 31, Rm B1-W30, non-Hodgkin’s lymphomas. Bethesda, MD 20892; Phone: 240-276-6560; Fax: 240-276-7892; 16. Rituximab does not References improve clinical outcome in a randomized phase III trial of 1. Changes in AIDS-related CHOP with or without rituximab in patients with HIV- lymphoma since the era of highly active antiretroviral therapy. Dose-reduced with dose-adjusted EPOCH: impact of antiretroviral therapy busulfan, cyclophosphamide, and autologous stem cell transplan- suspension and tumor biology. MYC aggressive dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse B-cell lymphomas: novel therapy of untreated Burkitt lym- large B-cell lymphoma. Swiss HIV Cohort Study: associations with immunodeficiency, Abstract 71. HIV-1-related Hodgkin outcome of lymphoma patients transferred to the intensive care lymphoma in the era of combination antiretroviral therapy: unit. Excellent immunological AIDS-defining cancers among HIV-infected patients compared recovery following CODOX-M/IVAC, an effective intensive with the general population in a large health district of northern chemotherapy for HIV-associated Burkitt’s lymphoma. Xicoy B, Ribera JM, Miralles P, et al; PETHEMA Group; non-Hodgkin lymphoma in the United States: disentangling the GESIDA Group; GMALL Group. Estimated HIV prevalence in the United combined antiretroviral therapy. Lymphocyte HIV-infected patients with plasmablastic lymphoma: results depletion during treatment with intensive chemotherapy for from the German AIDS-related lymphoma cohort study. Human immunodefi- and significance of severe toxicity in patients with human ciency virus-associated plasmablastic lymphoma. High-dose are the main cytogenetic alteration in plasmablastic lympho- zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus- mas. Intensive ase chain reaction in CSF for the diagnosis of AIDS-related chemotherapy with cyclophosphamide, doxorubicin, high-dose primary CNS lymphoma. AIDS-associated (CODOX-M/IVAC) for human immunodeficiency virus- primary central nervous system lymphoma (AIDS-PCNSL) associated Burkitt lymphoma. Oriol A, Ribera JM, Brunet S, del Potro E, Abella E, Esteve J. HIV and AIDS Malignancy Branch experience, 2004-2011 Highly active antiretroviral therapy and outcome of AIDS-related CROI 19. Hyperfractionated cyclophos- phoma treated with chemotherapy using doxorubicin, bleomy- phamide, vincristine, doxorubicin, and dexamethasone and cin, vinblastine, and dacarbazine in the highly active antiretro- highly active antiretroviral therapy for patients with acquired viral therapy era. Frenette2-4 Departments of 1Pediatrics, 2Medicine, and 3Cell Biology, and 4Ruth L. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY Recurrent and unpredictable episodes of vaso-occlusion are the hallmark of sickle cell disease. Symptomatic management and prevention of these events using the fetal hemoglobin–reactivating agent hydroxyurea are currently the mainstay of treatment. Discoveries over the past 2 decades have highlighted the important contributions of various cellular and soluble participants in the vaso-occlusive cascade. The role of these elements and the opportunities for therapeutic intervention are summarized in this review. Introduction reported to interact with the subendothelial matrix proteins (eg, Sickle cell disease (SCD) results from a single amino acid substitu- laminin, VWF). SS-RBC interactions with the vascular endothelium tion in the gene encoding the -globin subunit. Polymerization of may lead to the production of oxygen radicals by the endothelial cell deoxygenated sickle hemoglobin leads to decreased deformability and oxidant-dependent activation of the transcription factor NF- B. Through a complex interplay of adhesive NF- B up-regulates the transcription of various genes, including events among blood cells, these altered erythrocytes can obstruct the adhesion molecules such as E-selectin, VCAM-1, and ICAM-1 on vasculature, producing episodes of pain, hemolytic anemia, organ the surface of the endothelium. Circulating endothelial cells charac- injury, and early mortality. Although the molecular basis of SCD is terized by an activated phenotype (expression of VCAM-1 and well characterized, the complex mechanisms underlying vaso- E-selectin) and increased levels of plasma sVCAM-1 have also been reported and are reflective of continuous endothelial activation. Early studies using in vitro adhesion assays or a rat mesocecum ex vivo perfusion Both endothelial selectins, P-selectin and E-selectin, have been suggested to participate in VOC. Random precapillary obstruction by a small (also called ICAM-4) is an RBC adhesion receptor that can be number of dense SS-RBCs also contributes to VOC. A new model has been proposed in which the process is viewed as Propranolol (a -adrenergic receptor antagonist) and recombinant multistep and multicellular cascade driven by inflammatory stimuli LW infusions were shown to inhibit VOC, supporting the events and the adherence of leukocytes. Table 1 provides a summary of the noted in patients who report a painful crisis precipitated by emotional stress or physical exertion. SCD mice indeed exhibit a more can undergo autooxidation and precipitate on the inner surface of dramatic VOC phenotype when the experiment is carried out at the RBC membrane, causing membrane damage via iron-mediated nighttime. Other adhesive interactions proinflammatory environment that is exacerbated during episodes of require a soluble bridge molecule (eg, thrombospondin, VWF). Circulating leukocytes and platelets also have an activated SS-RBC adhesion molecules (eg, BCAM/LU, 4 1) have also been phenotype. Ischemia-reperfusion injury, release of free hemoglobin This article was selected by the Blood and Hematology 2013 American Society of Hematology Education Program editors for concurrent submission to Blood and Hematology 2013. This article is reprinted with permission from Blood. Evolving paradigm of sickle cell VOC Year Scientific observation Contribution 1910 James Herrick: Description of the first patient with sickle-shaped Original description RBCs on peripheral smear 1930 Shriver and Waugh: Venous circulation in a patient is enriched in A disease of the RBC sickle-shaped cells that regain normal shape upon reoxygenation 1949 Linus Pauling demonstrates that the disease originates from a A molecular disease of hemoglobin mutated hemoglobin molecule 1974 Hofrichter and Eaton: “delay time” for the initiation of rapid phase VOC is dependent on deoxy HbS concentration and transit time of deoxy-HbS polymerization of the RBCs 1979, 1980 Hebbel and Hoover: Increased propensity of SS-RBCs to Widened the scope of scientific studies outside the RBC. P- and E-selectin deficiency protects leukocytes in initiating VOC. P and E-selectins are important against TNF- induced VOC in mediating this interaction 2002 Reiter and Gladwin: Cell-free hemoglobin limits nitric oxide Nitric oxide depletion in SCD and its contribution to bioavailability in SCD vasculopathy 2003 Hines and Parise: Role for epinephrine in the regulation of Role of physiologic stress as a trigger for VOC BCAM/Lu dependant SS RBC adhesiveness 2004-2007 Zennadi and Telen: Epinephrine-induced activation of LW- Identifies -adrenergic receptor antagonism as a potential mediated sickle cell adhesion and VOC in a vivo mouse model therapeutic approach is blocked by propranolol 2009 Wallace and Linden: Ischemia reperfusion injury is amplified by Role of iNKT cells in triggering inflammation the activation of CD1d-restricted iNKT cells 2009 Hidalgo and Frenette: Role of secondary activation signals in Role of E-selectin as an activating signal, Src kinases and M 2 neutrophils 2009 Belcher and Vercellotti: Heme oxygenase-1 inhibits vascular Importance of heme in inflammation and VOC stasis in a murine model of SCD and heme secondary to RBC lysis, and increased production of reverses pulmonary dysfunction. Monocytes from SCD patients are activated in response to PlGF, secreting increased levels of TNF- , IL-1, and other chemokines. Treatment of SCD mice with anti-CD1d antibody creased expression of tissue factor, a primary activator of the to inhibit iNKT cell activation or treatment with CXCR3 inhibitors extrinsic pathway of coagulation. The generation of a novel synthetic pan-selectin inhibitor, GMI- Reduction of plasma levels of tissue factor in a sickle cell transgenic 1070, with maximal activity against E-selectin made it possible to mouse model results in decreased plasma levels of IL-6 and soluble further test this paradigm in VOC. Hofstra et al first reported that neutrophils could bind to phils predominantly express the “activating” Fc RIII receptor. In vivo evidence for this phenomenon was first reported tyrosine phosphatase-1 (SHP-1) in SCD mice. These interactions were increased or sustained VOC by overwhelming the adaptive mechanisms. Clinical sup- after exogenous administration of TNF- and frequently resulted in port for this concept comes, for example, from the observation complete VOC. Mice deficient in both P-selectin and E-selectin that delayed hemolytic transfusion reactions can precipitate VOC were unable to recruit leukocytes at the vessel wall and were events. Recent studies in a sickle cell murine model of hemolytic protected from TNF- –induced VOC. This suggested that the transfusion reaction have identified CXCL1 as a key inflamma- recruitment of the adherent leukocytes to activated endothelium was tory mediator of VOC. Exogenous administration of CXCL1 was necessary for the VOC process. Targeted inhibition of this pathway may represent and mediated by M 2 integrin a new therapeutic approach for VOC. When infused into SCD mice, cell-free hemoglobin beyond the initial events, allowing leukocytes to firmly adhere. Mice deficient in the of VOC is proposed in which adhesive interactions of SS-RBCs C3 complement protein, a ligand for Mac-1 integrin, have a partial and leukocytes to the endothelium play important roles in the reduction in RBC capture, suggesting the role of complement initiation of VOC17 (Figure 1). Although the exact mechanisms opsonization on the RBCs.

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