SWISS MED. WKLY: PLATELET TRANSFUSION

Review article | Published 13 December 2013, doi:10.4414/smw.2013.13885 Cite this as: Swiss Med Wkly. 2013;143:w13885 Platelet transfusion: basic aspects Andreas Holbroa, Laura Infantia, Jörg Sigleb, Andreas Busera a Blood Transfusion Centre, Swiss Red Cross, Basel, Switzerland b Blood Transfusion Centre, Swiss Red Cross, Aarau, Switzerland Summary Platelet transfusions have been shown to prevent major haemorrhage and improve survival in thrombocytopenic patients. Since then, advances in the preparation of platelet components, including the introduction of pathogen reduction techniques, have been achieved. The number of transfused platelet components is still growing owing to the increasing number of patients treated for haemato-oncological diseases. Additionally, indications have been extended, for example to patients with drug-induced platelet dysfunction. This review focuses on current platelet component production and storage techniques, including pathogen reduction, indications for platelet transfusion and safety issues including alloimmunisation and management of platelet refractoriness. Key words: platelets; transfusion; refractoriness, safety Introduction Platelet (PLT) transfusions were shown to reduce mortality from haemorrhage in patients with leukaemia in the 1950s [1]. Since then, although their use has grown and continues to grow [2, 3], a number of questions related to optimal preparation and storage of PLT components, and the indications, safety and efficacy of PLT transfusion have arisen. Nowadays PLT transfusions are an essential part of the supportive care of thrombocytopenic patients, such as those with haematological diseases. Additionally, inborn and acquired – mainly drug-induced – platelet dysfunctions can be overcome through transfusion of PLT components. In this review we provide an overview of the basic aspects of PLT transfusions and indicate the still open questions related to this practice. History The discovery of blood circulation by William Harvey in 1628 was the premise for transfusion medicine [4]. Afterwards, the first animal-to-animal transfusions were performed, soon leading to early experiments with animal-to-men transfusions in the mid of the 17th century. The first men-to-men transfusions were performed in 1818 [5]. In 1900, the discovery of the ABO blood group by Landsteiner was the cornerstone for further improvements in transfusion medicine [6]. As major and fatal haemorrhage due to thrombocytopenia was a leading cause of death in children with acute lymphoblastic leukaemia, major efforts were undertaken to improve the supportive care of thrombocytopenic patients [7]. The first studies of PLT transfusions showed not only feasibility but also efficacy in preventing major haemorrhage in thrombocytopenic patients, thus improving overall survival [1, 8]. PLT component production and clinical use were further improved by technical developments, improvements in apheresis techniques, development of PLT additive solutions and studies on storage conditions [9–12]. In the last few years, pathogen reduction techniques have been successfully implemented for PLT components and have reduced, in particular, the risks of morbidity and mortality due to bacterial contamination, one of the most feared consequences for the transfusion recipient [13, 14]. Nowadays, more than 4 million PLT components are transfused worldwide each year [2, 15]. Platelet components: manufacturing, storage and pathogen reduction Manufacturing of platelet components PLT components can be obtained either from whole blood donations or by single-donor apheresis. Both techniques have advantages and disadvantages (table 1) [16, 17]. PLT components derived from whole blood donations are produced by pooling either platelet rich plasma or buffy coats from multiple donors, using different sequential centrifugation steps [18]. The buffy coat pooling technique is the one most widely used in Europe. Whole blood donations are selected and centrifuged (hard spin) to separate plasma and red blood cells from the buffy coat layer containing leucocytes and PLTs. Four to six buffy coats of the same ABO blood group are pooled and a second centrifugation is performed (soft spin) to separate leucocytes and residual red blood cells from the PLTs. The remaining PLTs are resuspended in plasma or in a mixture of additive solution and plasma (about 2:1). For the production of single-donor apheresis PLT concentrates, various blood-separating devices are in use and licensed. Donor availability is a major limitation of this process. Although specific adverse effects of PLT apheresis are well described [19, 20], PLT apheresis is considered safe and can be safely performed even in donors with mild anaemia and low iron stores [21]. In Europe, virtually all PLT components are leucocyte-depleted in order to reduce side effects [22]. Overall, the properties and efficacy of the above-described PLT preparations are similar [23–27], although some centres still prefer single donor apheresis components for patients with haematological diseases in order to reduce donor exposure. Specifications of the final PLT product are stipulated by various regulations (Standards for Blood Banks and Transfusion Services, 26th edition. Bethesda, Maryland, AABB, 2009 and Guide to the Preparation, Use and Quality Assurance of Blood Components, 16th edition, Strasbourg, Council of Europe Publishing, 2010). In Switzerland the minimal PLT content has to be >2.4 x 1011/unit, and the number of residual leucocytes and red blood cells has to be <1 x 106/unit and <5 x 109/unit, respectively. Platelet storage In contrast to red blood cell concentrates, PLT components are stored at 22±2 °C under gentle agitation. Studies have shown a better transfusion response if they are stored at room temperature [10]. Because possibly contaminating bacteria can grow well under these conditions, duration of storage is limited to 4–7 days, depending on whether bacterial detection methods or pathogen reduction are used. The introduction of pathogen reduction techniques might solve this problem, but possibly at the price of a slight impairment of PLT function. After the introduction of universal pathogen reduction in Switzerland, PLT storage is now limited to a maximum of 7 days. PLT concentrates have to be agitated during storage in order to assure optimal oxygen and carbon dioxide exchange through the storage bag and to avoid a fall of pH, which would compromise PLT recovery and survival after transfusion [28]. Once delivered by the blood bank, PLT components can be kept safely at room temperature and removed from the rotator for at least 6 hours [29]. The short storage period of PLT components requires optimal inventory management by blood banks, best achieved through a close cooperation with the clinicians. Pathogen reduction Figure 1 Figure 1 Pathogen reduction with the INTERCEPT® method. Schematic representation of the mode of action of INTERCEPT®. Amotosalen intercalates within DNA/RNA. DNA/RNA crosslinks upon UVA irradiation. This blocks reproduction of pathogens and leucocytes. Courtesy of Cerus Corporation, Concord, CA, USA. Various pathogen reduction techniques have been developed in recent years [13]. In Switzerland, the amotosalen/UVA based INTERCEPT® (Intercept Blood System, Cerus Corporation, Concord, CA, USA) has been introduced nationwide and deemed mandatory in 2011. Amotosalen, a psoralen derivative, is added to PLT concentrates, binds to deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and – upon activation by ultraviolet-A (UVA) irradiation – crosslinks DNA and RNA. An absorbing device then removes residual amotosalen. With this technique, replication of viruses, bacteria, protozoa and residual leucocytes is reduced (fig. 1). To date, amotosalen, at the concentrations used, is reported to be nontoxic and nonmutagenic [30–33]. Concerns regarding the efficacy of pathogen-reduced PLT components in preventing bleeding have arisen. Studies showed discrepancies in PLT recovery, measured as the platelet corrected count increment (CCI; see below): some studies showed lower CCI of pathogen-reduced PLT compared with standard PLT components [34–36]. Other trials could not detect any significant difference [32, 37]. However, in all these studies the standard PLT components used for comparison were prepared in different additive solutions or in plasma, and were partly gamma irradiated, raising concerns about the influence of product factors on CCI. Our own study comparing single-donor apheresis PLTs treated with amotosalen/UVA versus gamma-irradiated PLTs, both resuspended in the same additive solution (PAS III), showed no significant differences in CCI [38]. Clinical endpoints, measured as incidence and severity of World Health Organisation (WHO) grade 2 bleeding complications, were shown to occur slightly more frequently in patients supported with pathogen-reduced PLT [36]. However, there was no significant difference in severe bleeding complications, thus arguing in favour of pathogen-reduced PLT components, which are associated with improved safety concerning microbial contamination [39]. Two different meta-analyses [40, 41] reached conclusions different from the available studies as to the risk of WHO grade 2 bleeding. However, WHO grade 2 bleeding might not be the right surrogate outcome in PLT transfusions studies [42]. Since the nationwide introduction of pathogen reduction of PLT components in Switzerland in 2011, no transfusion-transmitted infection related to bacterial contamination has been reported to the national haemovigilance office, whereas the incidence of mortality due to bacterially contaminated PLT transfusions was estimated to be 1.5 cases/year before implementation of this method [3]. Two other methods are also on the way; however they are not yet licensed for use in Switzerland. Mirasol® (Terumo BCT, Tokyo, Japan) uses riboflavin, which associates with DNA/RNA and mediates an oxygen-independent electron transfer upon UV exposure causing irreversible damage to nucleic acids [43, 44]. Theraflex® (Macopharma, Tourcoing, France) uses UVC without any additional photochemically active compound [45]. The clinical experience with PLT components treated with these methods is still limited. Table 1: Comparison of platelet components produced from whole blood donations or by apheresis. Advantages Disadvantages Whole-blood derived PLTs Availability PLT dose modification Avoids product waste No additional donor risk Multiple donor exposure Difficult HLA/HPA matching Apheresis PLTs Less donor exposure Automation and standardisation HLA/HPA matching Donor availability Higher production costs Limited PLT dose Donor risk from apheresis procedure HLA = human leucocyte antigen; HPA = human platelet antigen; PLT = platelet Indications for platelet transfusions PLTs can be transfused in order to prevent bleeding (prophylactic indication) or to stop bleeding (therapeutic indication) both in thrombocytopenic and in patients with normal PLT counts. The vast majority of PLT transfusions are performed in thrombocytopenic haemato-oncological patients. Drug-induced PLT dysfunctions, such as in patients undergoing major cardiovascular surgery or, less frequently, due to inborn defects, are further indications for PLT transfusions. In patients with thrombotic thrombocytopenic purpura (TTP) and heparin-induced thrombocytopenia (HIT), PLT transfusions are in general indicated only in the case of severe bleeding. For prophylactic PLT transfusions, many studies have shown that in patients with chronic stable thrombocytopenia a lower threshold of 5–10 x 109/l is safe [46, 47]. Today this threshold is widely accepted by clinicians and is generally indicated as standard in the various published guidelines for PLT transfusion [48, 49]. Based on the available studies and guidelines, every institution should establish its own transfusion triggers in collaboration with the blood bank and transfusion specialists. The efficacy of prophylactic PLT transfusions in thrombocytopenic patients has been evaluated in studies comparing prophylactic and therapeutic PLT transfusions regimens in haemato-oncological patients. A recent trial showed an increase in severe and fatal haemorrhage in patients with acute leukaemia who received therapeutic rather than prophylactic transfusions [50]. This finding was confirmed by another recent noninferiority study in haematological patients, who did not receive prophylactic PLT transfusions when morning PLT counts were less than 10 x 109/l, but only in the case of bleeding [51]. Factors affecting efficacy of platelet transfusions Assessment of PLT transfusion efficacy is a major challenge. Several criteria have been developed and evaluated, most of them including the post-transfusion PLT count (fig. 2). Figure 2 Figure 2 Methods for assessment of platelet transfusion efficacy. Clinical endpoints (i.e. bleeding) are the most important method for evaluating effectiveness of PLT transfusions. Different scores have been developed with the goal of objectively assessing bleeding, but lack of standardisation of these methods is still a major problem [52, 53]. It has to be emphasised that CCI, the most widely used marker for measuring efficacy of PLT transfusions, does not necessarily correlate with clinical bleeding (see below, “platelet transfusion refractoriness”). Various factors have a direct or indirect influence on the efficacy of PLT transfusions: Product factors Platelet dose In Switzerland the standard therapeutic adult dose is more than 2.4 x 1011 PLTs per unit. This varies according to different guidelines and national transfusion policies. However, PLT dose per unit has no effect on the incidence of bleeding in patients undergoing haematopoietic stem-cell transplantation or chemotherapy for haematological cancers or solid tumours [54]. ABO compatibility ABO mismatched transfusions have a lower PLT recovery than ABO-compatible PLT transfusions [55]. Guidelines recommend that, whenever possible, PLT units issued for transfusion should be of the same ABO blood group as the patient’s. Other Other product factors include storage time, resuspension of PLT in additive solutions vs plasma, PLT irradiation and pathogen reduction. Interestingly, ABO blood group, PLT storage time and PLT source, which all have a moderate impact on CCI, had no impact on clinical bleeding [39]. Patient factors Patient’s gender, height and weight, several clinical conditions (listed in table 2), and drugs all have an impact on transfusion efficacy (see below, “platelet transfusion refractoriness”). On the basis of standard CCI or percent PLT recovery calculations, male patients showed inferior recovery rates, irrespective of donor sex. However, using an adjusted percent of platelet recovery, which takes into account differences in blood volume between males and females (according to Nadler’s formula), neither donor nor recipient sex played any role in PLT recovery after transfusion in non-HLA-immunised patients [56]. Table 2: Factors associated with platelet transfusion refractoriness. A. Nonimmune factors: – Clinical factors: fever, infection/sepsis, splenomegaly, DIC, GVHD, bleeding – Drugs*: vancomycin, heparin, GPIIb/IIIa antagonists, ... – Product factors: storage duration, platelet dose, ABO compatibility, use of additive solution, irradiation, pathogen reduction – Patient factors: sex, weight/height, history of pregnancy and transfusions B. Immune factors: – ABO incompatibility – HLA-antibodies – HPA antibodies DIC = disseminated intravascular coagulation; GVHD = graft-versus-host disease; HLA = human leucocyte antigen; HPA = human platelet antigen * See also reference [58]. Platelet transfusion refractoriness Figure 3 Figure 3 Proposed algorithm for the management of patients with platelet transfusion refractoriness. DIC = disseminated intravascular coagulation; GVHD = graft-versus-host disease; HLA = human leucocyte antigen; HPA = human platelet antigen; PLT = platelet components Definitions: – HLA-identical: same class I HLA antigens (HLA-A and HLA-B) patient and donor – HLA-compatible: according to HLA matchmaker (see text) – HLA-permissive: recipient has no HLA antibodies against donor HLA antigens As described above, assessment of PLT transfusion efficacy is very important. Fig. 2 shows different criteria for evaluating PLT transfusion efficacy. Platelet transfusion refractoriness is defined as an insufficient post-transfusion PLT count increment. Usually it is defined as two or more consecutive CCIs of <7.5 at 1 hour or a CCI <4.5 18‒24 hours after transfusion of ABO-identical PLT concentrates less than 3 days old (fig. 2) [57]. However, in daily routine practice the provision of these products (ABO-compatible and younger than 3 days) may be difficult and they are not always readily available. Nonimmune and immune factors are associated with PLT transfusion refractoriness (table 2) [58, 59]. Nonimmune factors lead to increased PLT consumption. Bleeding, infection/sepsis, splenomegaly and graft-versus-host disease (GVHD) in patients receiving allogeneic haematopoietic stem-cell transplantation are the most common nonimmune causes for refractoriness to PLT transfusions. Drugs are also an important cause and should be considered in the evaluation of patients with PLT transfusion refractoriness. Immune factors are responsible for PLT transfusion refractoriness in approximately 20% of cases, with HLA antibodies being most commonly involved [58]. Less frequently, human platelet antigen (HPA) antibodies – or a combination of HLA and HPA antibodies – cause transfusion refractoriness. Minor histocompatibility antigens play an important role in haematopoietic stem-cell transplantation [60]. H-Y proteins are ubiquitously expressed Y chromosome-encoded minor histocompatibility antigens. These antigens however have no influence on the outcome of PLT transfusions [56]. In refractory patients, nonimmune aetiologies have first to be excluded (table 2 and fig. 3). If immune PLT transfusion refractoriness is suspected, a search for HLA-antibodies should be initially performed. If HLA antibodies are detected, various options for the selection of suitable PLT units are available. All of them require HLA class I typing of PLT donors: (A) Selection of HLA-identical PLT components from HLA-matched apheresis donors (B) Selection of HLA-compatible PLT products according to cross-reactive groups (CREGs) or in silico matching (HLA matchmaker). HLA matchmaker is a computer algorithm that identifies compatibility at the epitope level, which is determined by short sequences of polymorphic amino acids [61, 62]. (C) Selection of HLA-permissive PLT products, avoiding the recipient HLA antibody specificities by selection of donors lacking the corresponding antigens. Provision of HLA permissive PLT products is especially useful if HLA typing of the recipient is not available. It is important to note that the presence of HLA-antibodies is – on the other hand - not always associated with PLT transfusion refractoriness. An in-vitro method to test compatibility is a PLT crossmatch, i.e., testing the patient`s serum against donor PLTs. Fig. 3 shows a proposed algorithm, which may help in the case of PLT transfusion refractoriness [63]. Safety of platelet transfusions PLT transfusions can be associated with various transfusion reactions (see table 3) [64]. Febrile transfusion reactions are the most frequently observed side effects after PLT transfusions [3, 65]. Immune-haemolytic complications and microbial contamination of PLT components have to be excluded. Cytokines in PLT concentrates and anti-HLA antibodies of the recipient are the main causes for febrile transfusion reactions [66]. Allergic reactions are generally mild. Foreign donor plasma antigens are responsible for these. Patients with IgA deficiency and anti-IgA antibodies are at particular risk for severe anaphylactic transfusion reactions [67, 68]. In patients with IgA deficiency, these can range from urticarial to severe anaphylactic reactions including hypotension, dyspnoea and shock [69]. Haemolysis due to donor isohaemagglutinins (anti-A and anti-B) can occur after PLT transfusions [70, 71]. As already mentioned above, the risk of microbial contamination of PLT components can be reduced by pathogen reduction techniques [13]. Before the introduction of universal pathogen reduction in Switzerland, bacterial contamination occurred with an incidence of 1:3,000–1:10,000 [14]. Sepsis due to bacterial contamination is one of the most feared transfusion reactions as it can be fatal. Transfusion related lung injury (TRALI) is a severe pulmonary transfusion complication, caused by HLA and human neutrophil antibodies against recipient antigens [72]. Storage of PLT in PAS has shown to reduce the incidence of TRALI [73, 86]. Transfusion associated circulatory overload (TACO) is seldom associated with isolated PLT transfusions. It occurs after rapid transfusion of large volumes of blood, as in cases of massive transfusion. Older patients and patients with cardiovascular diseases and renal failure are at increased risk of TACO [74]. Transfusion associated graft-versus-host disease (taGVHD) occurs in severely immunosuppressed patients after engraftment of donor lymphocytes and is often fatal. It can be prevented by gamma irradiation of PLT concentrates (25–30 Gy). Pathogen reduction techniques are equivalent to gamma irradiation in this respect [75]. Alloimmunisation can be a problem in patients receiving multiple transfusions. It is related to residual red blood cells and leucocytes in the PLT components, as well as PLT antigens. PLTs express carbohydrate blood groups like ABO, P, I and Lewis antigens [76]. Additionally HLA class I molecules are expressed, as PLT contain messenger RNA for the synthesis of these molecules [77]. PLT-specific antigens (HPAs) are glycoproteins involved in haemostasis [78]. Both HLA and HPA can stimulate the production of alloantibodies and thus cause PLT transfusion refractoriness. Additionally, HPA can cause neonatal alloimmune thrombocytopenia (NAIT), caused by maternal alloantibodies against paternally inherited HPA of the foetus. These HPA alloantibodies pass the placenta and are responsible for severe thrombocytopenia in the foetus and the newborn [79]. Although PLT express HLA class I antigens, the main cause for the development of HLA antibodies in chronically transfused patients are leucocytes contaminating PLT products. Universal leucoreduction is thus an efficient measure for the prevention of HLA immunisation [80–82]. Additionally, a careful evaluation of transfusion indications in order to avoid unnecessary exposure to antigens is of primary importance. Besides transfusions, HLA and HPA antibodies can develop during pregnancy, which is the most important cause of alloimmunisation [83]. Alloimmunisation against rhesus (Rh) D antigen can also occur following PLT transfusions, although PLTs do not express Rh antigens. Alloimmunisation against red blood cell antigens due to PLT transfusions are related to residual red blood cells in PLT products. Transfusion of Rh D negative PLT components is therefore especially important in Rh D negative female recipients of childbearing age [84]. In the case of transfusion of Rh D positive PLT concentrates to a Rh D negative recipient, which is sometimes unavoidable because of inventory shortages, administration of Rh immunglobulin has to be considered (120–300 μg IV). Table 3: Transfusion reactions after platelet transfusion. Cause Prevention Febrile transfusion reaction Cytokines; recipient HLA antibodies Leucocyte reduction Allergy/anaphylaxis Anti-IgA antibodies in patients, donor plasma antigens Antihistamines, steroids, washed PLT products Haemolysis Donor isohaemagglutinins ABO identical transfusion, washed PLT products, use of PAS Microbial contamination Viruses, bacteria, parasites, fungi Donor selection and testing, pathogen reduction, leucocyte reduction (CMV), limitation of storage duration Transfusion associated lung injury (TRALI) Donor HLA and HNA antibodies Male donors, exclusion of donors with HLA and/or HNA antibodies Transfusion associated circulatory overload (TACO) Volume overload Identify patients at risk (neonates, old patients, patients with cardiac and renal diseases), diuretics Transfusion associated GVHD Donor lymphocytes in immunosuppressed patients Gamma irradiation (25‒30 Gy), pathogen reduction Alloimmunisation HLA antigens on residual leucocytes HPA antigens on PLT Residual RBC in PLT component Leucocyte reduction, donor selection, Anti-D prophylaxis CMV = cytomegalovirus; GVHD = graft-versus-host disease; Gy = Gray (J/kg); HLA = human leucocyte antigen; HNA = human neutrophil antigen; PAS = platelet additive solutions; PLT = platelets; RBC = red blood cell Future directions As demand for PLT transfusions will continue to increase, donor availability poses a major challenge for blood banks. For optimal management of PLT supply, a close collaboration between clinicians, blood banks and transfusion specialists is mandatory. Alternative pathogen reduction techniques are under development and may contribute substantially to safer PLT transfusions. Additionally, studies on alternatives to PLT transfusions and other methods to improve haemostasis in bleeding patients are under investigation. Until then, a personalised and individualised patient transfusion management is the safest and most efficient approach to patients requiring PLT support. Development of PLTs from haematopoietic stem cells, human embryonic stem cells and human induced pluripotent stem cells and expansion of ex-vivo generated PLT are further exciting fields of research [85]. Funding / potential competing interests: No financial support and no other potential conflict of interest relevant to this article was reported. Correspondence: Andreas Holbro, MD, Blood Transfusion Centre, Swiss Red Cross, Hebelstrasse 10, CH-4031 Basel, Switzerland, andreas.holbro[at]usb.ch

BREAKTHROUGH PRIZES ($3-million each)

The Breakthrough Prize in Life Sciences Foundation announced that Howard Hughes Medical Institute (HHMI) investigator Richard P. Lifton of Yale University is among the six scientists awarded the Life Sciences Prize for excellence in research aimed at curing intractable diseases and extending human life. The Breakthrough Prizes recognize pioneering work in physics and genetics, cosmology, and neurology and mathematics. Each prize carries an award of $3 million. Lifton, who has been an HHMI investigator since 1994, uses genetic approaches to identify the genes and pathways that contribute to common human diseases, including cardiovascular, renal, and bone disease. He was honored by the foundation for the discovery of genes and biochemical mechanisms that cause hypertension. More than two decades ago, when Lifton first proposed using genetic methods to study the causes of high blood pressure, his approach was not uniformly accepted. Such a complicated condition, critics thought, would not lend itself to traditional genetic tactics, which try to link a disease to alterations in a single gene. Since then, Lifton has proved his detractors wrong many times over. Lifton has identified more than 20 genes associated with blood pressure, cardiovascular disease, and bone density, and he has characterized mutations that cause either extreme hypertension (high blood pressure) or hypotension (low blood pressure) in people. More significantly, he has shown that severe blood pressure problems can be caused by mutations in genes that regulate the amount of sodium chloride the kidney allows to flow into the blood. When these genes falter in severe hypertension cases, salt levels rise, blood volume increases, the heart pumps harder, and blood pressure surges. With excessive hypotension, the opposite occurs. Today, his findings have changed how doctors treat hypertension, which affects approximately one billion people worldwide and is the most prevalent cardiovascular disease risk factor. The foundation also recognized HHMI alumni investigator James Allison at the University of Texas MD Anderson Cancer Center for the discovery of T cell checkpoint blockade as effective cancer therapy. Allison was an HHMI investigator from 2004-2012. The six winners of the 2014 Breakthrough Prize in Life Sciences are: • James Allison, MD Anderson Cancer Center, for the discovery of T cell checkpoint blockade as effective cancer therapy. • Mahlon DeLong, Emory University, for defining the interlocking circuits in the brain that malfunction in Parkinson's disease. This scientific foundation underlies the circuit-based treatment of Parkinson's disease by deep brain stimulation. • Michael Hall, University of Basel, for the discovery of Target of Rapamycin (TOR) and its role in cell growth control. • Robert Langer, David H. Koch Institute Professor at the Massachusetts Institute of Technology, for discoveries leading to the development of controlled drug-release systems and new biomaterials. • Richard Lifton, Yale University; Howard Hughes Medical Institute, for the discovery of genes and biochemical mechanisms that cause hypertension. • Alexander Varshavsky, California Institute of Technology, for discovering critical molecular determinants and biological functions of intracellular protein degradation. Prize recipients are invited to serve on the selection committee to select recipients of future prizes. Last year, HHMI investigators Cornelia I. Bargmann at the Rockefeller University, Charles L. Sawyers at Memorial Sloan-Kettering Cancer Center and Bert Vogelstein at Johns Hopkins University School of Medicine were awarded the Breakthrough Prize in Life Sciences. Founded in 2013, the Breakthrough Prize in Life Sciences Foundation is a not-for-profit corporation dedicated to advancing breakthrough research, celebrating scientists and generating excitement about the pursuit of science as a career. The Foundation was founded by Sergey Brin and Anne Wojcicki, Mark Zuckerberg and Priscilla Chan, Jack Ma and Cathy Zhang, and Yuri and Julia Milner, and is chaired by Arthur Levinson, who is also chairman of Genenand Apple.

St.MARTIN.(FRENCH part of island) CHIKUNGUNYA VIRUS

Notice to Public Health Officials and Clinicians: Recognizing, Managing, and Reporting Chikungunya Virus Infections in Travelers Returning from the Caribbean Summary On December 7, 2013, the World Health Organization (WHO) reported the first local (autochthonous) transmission of chikungunya virus in the Americas. As of December 12th, 10 cases of chikungunya have been confirmed in patients who reside on the French side of St. Martin in the Caribbean. Laboratory testing is pending on additional suspected cases. Onset of illness for confirmed cases was between October 15 and December 4. At this time, there are no reports of other suspected chikungunya cases outside St. Martin. However, further spread to other countries in the region is possible. Chikungunya virus infection should be considered in patients with acute onset of fever and polyarthralgia, especially those who have recently traveled to the Caribbean. Healthcare providers are encouraged to report suspected chikungunya cases to their state or local health department to facilitate diagnosis and to mitigate the risk of local transmission. Background Chikungunya virus is a mosquito-borne alphavirus transmitted primarily by Aedes aegypti and Aedes albopictus mosquitoes. Humans are the primary reservoir during epidemics. Outbreaks have been documented in Africa, Southern Europe, Southeast Asia, the Indian subcontinent, and islands in the Indian and Pacific Oceans. Prior to the cases on St. Martin, the only chikungunya cases identified in the Americas were in travelers returning from endemic areas. Clinical Disease A majority of people infected with chikungunya virus become symptomatic. The incubation period is typically 3–7 days (range, 2–12 days). The most common clinical findings are acute onset of fever and polyarthralgia. Joint pains are often severe and debilitating. Other symptoms may include headache, myalgia, arthritis, or rash. Persons at risk for more severe disease include neonates (aged <1 month) exposed intrapartum, older adults (e.g., ≥ 65 years), and persons with underlying medical conditions (e.g., hypertension, diabetes, or cardiovascular disease). Diagnosis Chikungunya virus infection should be considered in patients with acute onset of fever and polyarthralgia who recently returned from the Caribbean. Laboratory diagnosis is generally accomplished by testing serum to detect virus, viral nucleic acid, or virus-specific immunoglobulin M (IgM) and neutralizing antibodies. During the first week of illness, chikungunya virus infection can often be diagnosed by using viral culture or nucleic acid amplification on serum. Virus-specific IgM and neutralizing antibodies normally develop toward the end of the first week of illness. To definitively rule out the diagnosis, convalescent-phase samples should be obtained from patients whose acute-phase samples test negative. Chikungunya virus diagnostic testing is performed at CDC, two state health departments (California and New York), and one commercial laboratory (Focus Diagnostics). Healthcare providers should contact their state or local health department to facilitate testing. Treatment No specific antiviral treatment is available for chikungunya fever. Treatment is generally palliative and can include rest, fluids, and use of analgesics and antipyretics. Because of similar geographic distribution and symptoms, patients with suspected chikungunya virus infections also should be evaluated and managed for possible dengue virus infection. People infected with chikungunya or dengue virus should be protected from further mosquito exposure during the first few days of illness to prevent other mosquitoes from becoming infected and reduce the risk of local transmission. Prevention No vaccine or preventive drug is available. The best way to prevent chikungunya virus infection is to avoid mosquito bites. Use air conditioning or screens when indoors. Use insect repellents and wear long sleeves and pants when outdoors. People at increased risk for severe disease should consider not traveling to areas with ongoing chikungunya outbreaks.

TORONTO: MEDICAL SERVICES for visitors.

FROM PHYSICIAN CONTRIBUTOR IN TORONTO AVOID LOCAL ER DEPTS. WAITING TIME 4-6 hrs. Nurse triage. ADVISE LIMO RIDE ($400)1.5 - 2 hr. to Mount St.Mary Hospital,Lewiston, NY. Quick access to Specialists, MRI etc. For general medical advice CLEVELAND CLINIC CANADA, (30,000 sq.ft.)@ BROOKFIELD PLACE, 181 BAY ST. (also entrance YONGE ST.) 416-507-6600 Same building as Hockey Hall of Fame & MARCHE Swiss Restaurant. Connected to USA Cleveland clinics. (Near Fairmont ROYAL YORK Hotel.) MEDCAN Private clinic,150 YORK St.(@ Adelaide)416-350-5900 (Mid-Town location)Near to HILTON & SHERATON Hotels.) No Private Hospitals in Ontario (Quebec has Private Medicine)

USA NIH Dr.Ola LANDGREN MD PhD (Karolinska,Stockholm)

C. Ola Landgren, M.D., Ph.D. Lymphoid Malignancies Branch Senior Investigator Center for Cancer Research National Cancer Institute Bulding 10, Room 13N240 Bethesda, MD 20892-1906 Phone: 301-496-0670 Fax: 301-402-0172 E-Mail: landgreo@mail.nih.gov Dr. Landgren received his M.D. in 1995 from the Karolinska Institute (Stockholm, Sweden). Following clinical training as a hematology/internal medicine specialist physician and receipt of a Ph.D. focusing on diagnostics and prognostics in Hodgkin lymphoma (2002) at Karolinska Institute in Sweden, he worked as an attending physician and conducted clinical research on lymphoproliferative malignancies and related precursors. In 2004, he came to the National Cancer Institute, Genetic Epidemiology Branch, DCEG, where he worked as an Investigator before he joined the Medicial Oncology Branch. Dr. Landgren's major research interests are in the treatment, causation, diagnostics and prognostics, and natural history of multiple myeloma and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). He also studies related hematologic malignancies and their precursors states (including chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis (MBL); Waldenstrom's macroglobulinemia and IgM MGUS), as well as myeloproliferative neoplasms. His research focuses on treatment-, host-, disease-, and immune-related factors in the pathway from precursor to full-blown malignancy, and their relation to outcome. Research Dr. Landgren's research interests include: - Examination of novel therapies for multiple myeloma and its precursor states - Identification of predictors for progression; from precursor to malignancy, and outcome - Definition of the roles for infectious antigens, inflammation, chronic immune stimulation, and immune modulation in hematopoietic carcinogenesis - Assessment and definition of host- and disease-related diagnostic/prognostic markers This page was last updated on 10/28/2013.

DAILY MAIL: Death of HPV vaccine pioneer D.Anne SZAREWSKI

Scientist who pioneered cervical cancer vaccine found dead by husband at home after he warned she was working too hard By Paul Bentley and Sara Smyth PUBLISHED: 19:35 GMT, 8 December 2013 | UPDATED: 01:51 GMT, 9 December 2013 The scientist who pioneered the cervical cancer vaccine was found dead by her husband at their £2million home after he warned she was ‘heading for a crisis’ by working too hard. In August he found her dead in their four-bedroom home in West Hampstead, North London, after he spent two hours drilling through a door she had locked from the inside. She was found with high levels of an anti-malarial drug in her bloodstream, but doctors said this was not thought to have caused her death. Dr Szarewski, who used her maiden name, was preparing for five international work trips and had been complaining that she was experiencing all-over body pains with ‘mounting intensity’. University lecturer: Dr Anne Szarewski's discovery has saved thousands of lives Mr Venter,(husband) 63, told the inquest into her death at St Pancras Coroner’s Court: ‘I was in the habit of telling her that she was heading for a crisis. I just realised she couldn’t maintain the pace that she was setting for herself.’ Dr Szarewski is credited with discovering the link between the human papillomavirus and cervical cancer, leading to a vaccine for HPV – the first-ever vaccine against any form of cancer – which is now routinely given to girls across the country. Born in London to Polish parents, she studied medicine at Middlesex Hospital before working at the Whittington Hospital in Highgate, North London. Latterly she worked as a gynaecologist at the Margaret Pike Centre in King’s Cross, was a clinical lecturer at the Wolfson Institute, Queen Mary, University of London, and also worked for Cancer Research. Her husband of ten years, a former political journalist from South Africa, told the court the couple slept in separate bedrooms because they enjoyed their own space. Mr Venter said that he woke up on August 24 after a night at the theatre and when his wife did not come down for breakfast he was initially pleased that she was having a well-deserved lie-in. When she still had not emerged at 2pm, however, he became concerned and found her bedroom door was locked. After two hours trying to open it with an electric drill, he forced his way inside. ‘As I entered the room I saw her on the bed and I realised straight away that she was dead,’ he said. The couple’s home contained two-and-a-half cupboards of medication, a collection Mr Venter described as one of his wife’s ‘charming eccentricities’. A pathologist’s report read out to the inquest found the scientist died from PANCREATITIS The anti-malaria drug Chloroquine was discovered in her blood. It is known to be highly toxic in overdose quantities. A packet was later found in the house but this is not thought to have been the cause of death and the coroner recorded a verdict of death by natural causes. Read more: http://www.dailymail.co.uk/news/article-2520360/Scientist-Anne-Szarewski-pioneered-cervical-cancer-vaccine-dead-husband-home.html#ixzz2mwLSq4XP Follow us: @MailOnline on Twitter | DailyMail on Facebook

50th anniversary of development of Measles vaccine by Duke Univ. Emeritus Prof. S.L.KATZ

Press Release Embargoed until: Thursday, December 5, 2013 at 12:00 noon ET Contact: Media Relations (404) 639-3286 Measles Still Threatens Health Security On 50th Anniversary of Measles Vaccine, Spike in Imported Measles Cases Fifty years after the approval of an extremely effective vaccine against measles, one of the world’s most contagious diseases, the virus still poses a threat to domestic and global health security. On an average day, 430 children – 18 every hour – die of measles worldwide. In 2011, there were an estimated 158,000 measles deaths. In an article published on December 5 by JAMA Pediatrics, CDC’s Mark J. Papania, M.D., M.P.H., and colleagues report that United States measles elimination, announced in 2000, has been sustained through 2011. Elimination is defined as absence of continuous disease transmission for greater than 12 months. Dr. Papania and colleagues warn, however, that international importation continues, and that American doctors should suspect measles in children with high fever and rash, “especially when associated with international travel or international visitors,” and should report suspected cases to the local health department. Before the U.S. vaccination program started in 1963, measles was a year-round threat in this country. Nearly every child became infected; each year 450 to 500 people died each year, 48,000 were hospitalized, 7,000 had seizures, and about 1,000 suffered permanent brain damage or deafness. People infected abroad continue to spark outbreaks among pockets of unvaccinated people, including infants and young children. It is still a serious illness: 1 in 5 children with measles is hospitalized. Usually there are about 60 cases per year, but 2013 saw a spike in American communities – some 175 cases and counting – virtually all linked to people who brought the infection home after foreign travel. “A measles outbreak anywhere is a risk everywhere,” said CDC Director Tom Frieden, M.D., M.P.H. “The steady arrival of measles in the United States is a constant reminder that deadly diseases are testing our health security every day. Someday, it won’t be only measles at the international arrival gate; so, detecting diseases before they arrive is a wise investment in U.S. health security. Eliminating measles worldwide has benefits beyond the lives saved each year. Actions taken to stop measles can also help us stop other diseases in their tracks. CDC and its partners are building a global health security infrastructure that can be scaled up to deal with multiple emerging health threats. Currently, only 1 in 5 countries can rapidly detect, respond to, or prevent global health threats caused by emerging infections. Improvements overseas, such as strengthening surveillance and lab systems, training disease detectives, and building facilities to investigate disease outbreaks make the world -- and the United States -- more secure. “There may be a misconception that infectious diseases are over in the industrialized world. But in fact, infectious diseases continue to be, and will always be, with us. Global health and protecting our country go hand in hand,” Dr. Frieden said. Today’s health security threats come from at least five sources: The emergence and spread of new microbes The globalization of travel and food supply The rise of drug-resistant pathogens The acceleration of biological science capabilities and the risk that these capabilities may cause the inadvertent or intentional release of pathogens Continued concerns about terrorist acquisition, development, and use of biological agents. “With patterns of global travel and trade, disease can spread nearly anywhere within 24 hours,” Dr. Frieden said. “That’s why the ability to detect, fight, and prevent these diseases must be developed and strengthened overseas, and not just here in the United States.” The threat from measles would be far greater were it not for the vaccine and the man who played a major role in creating it, Samuel L. Katz, M.D., emeritus professor of medicine at Duke University. Today, CDC is honoring Dr. Katz 50 years after his historic achievement. During the ceremony, global leaders in public health are highlighting the domestic importance of global health security, how far we have come in reducing the burden of measles, and the prospects for eliminating the disease worldwide. Measles, like smallpox, can be eliminated. However, measles is so contagious that the vast majority of a population must be vaccinated to prevent sustained outbreaks. Major strides already have been made. Since 2001, a global partnership that includes the CDC has vaccinated 1.1 billion children. Over the last decade, these vaccinations averted 10 million deaths – one fifth of all deaths prevented by modern medicine. “The challenge is not whether we shall see a world without measles, but when,” Dr. Katz said. “No vaccine is the work of a single person, but no single person had more to do with the creation of the measles vaccine than Dr. Katz,” said Alan Hinman, M.D., M.P.H., Director for Programs, Center for Vaccine Equity, Task Force for Global Health. “Although the measles virus had been isolated by others, it was Dr. Katz’s painstaking work passing the virus from one culture to another that finally resulted in a safe form of the virus that could be used as a vaccine.”