BMJ:COITUS PORTALIS

Like a virgin (mother): analysis of data from a longitudinal, US population representative sample survey BMJ 2013; 347 doi: http://dx.doi.org/10.1136/bmj.f7102 (Published 17 December 2013) Cite this as: BMJ 2013;347:f7102 Amy H Herring, professor12,DEPT.BIOSTATISTICS,U.NORTH CAROLINA Samantha M Attard, PhD candidate23, Penny Gordon-Larsen, professor23, William H Joyner, the reverend4, Carolyn T Halpern, professor25 Author Affiliations Correspondence to: A H Herring amy_herring@unc.edu Abstract Objective To estimate the incidence of self report of pregnancy without sexual intercourse (virgin pregnancy) and factors related to such reporting, in a population representative group of US adolescents and young adults. Design Longitudinal, population representative sample survey. Setting Nationally representative, multiethnic National Longitudinal Study of Adolescent Health, United States. Participants 7870 women enrolled at wave I (1995) and completing the most recent wave of data collection (wave IV; 2008-09). Main outcome measures Self reports of pregnancy and birth without sexual intercourse. Results 45 women (0.5%) reported at least one virgin pregnancy unrelated to the use of assisted reproductive technology. Although it was rare for dates of sexual initiation and pregnancy consistent with virgin pregnancy to be reported, it was more common among women who signed chastity pledges or whose parents indicated lower levels of communication with their children about sex and birth control. Conclusions Around 0.5% of women consistently affirmed their status as virgins and did not use assisted reproductive technology, yet reported virgin births. Even with numerous enhancements and safeguards to optimize reporting accuracy, researchers may still face challenges in the collection and analysis of self reported data on potentially sensitive topics.

SWEDEN:PANDEMRIX & NARCOLEPSY

to promed-post, promed-edr-post INFLUENZA (71): SWEDEN, PANDEMRIX VACCINE AND NARCOLEPSY ******************************************************** A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: Thu 19 Dec 2013 Source: The Local (Sweden) [edited] Scientists believe they have found the cause of the narcolepsy cases uncovered after Sweden's inoculation drive against swine flu [influenza H1N1 pdm09]. The jab may have set off an auto-immune response that caused brain damage. The Pandemrix vaccine likely "fooled" the brain to attack cells in the brain that regulate sleeping patterns. The cells in question produce a protein called hypocretin, which regulates whether a person is awake or asleep. Sweden offered its citizens the vaccine against swine flu during the epidemic in 2009-2010, which claimed between 9 to 31 Swedes' lives. Experts at the time said they feared the disease would be as big a killer as the Spanish flu in the late 1910s, when an estimated 3-5 percent of the world's population succumbed. Since the inoculation drive, however, more than 100 Swedes -- many of them teenagers -- have developed narcolepsy. The Swedish Medical Products Agency (Lakemedelsverket) ordered a massive study to determine whether the vaccine had any connection to narcolepsy. It compared 3.3 million vaccinated Swedes with 2.5 million who were not vaccinated. "We can see that over the whole study period, we have 126 cases of those vaccinated getting narcolepsy," Ingemar Person, professor behind the study, said in a statement on Tuesday [17 Dec 2013]. "There were 20 cases among those not vaccinated. We're talking about a 3-fold increase in risk." The scientists at the Stanford School of Medicine have now said that a part of the vaccine had some similarities to parts of hypocretin that trigger the immune system. The scientists said that the ensuing reaction meant the body's own immune system could not see the difference between the hypocretin and the parts of the flu virus that the body was meant to attack. The end result: The body attacked the part of the brain that regulates sleeping patterns. "We have long thought that auto-immune diseases don't afflict the brain, but that is obviously not correct," according to the Stanford researcher Emmanuel Mignot. Narcolepsy is a chronic nervous system disorder that causes excessive drowsiness, often causing people to fall asleep uncontrollably and, in more severe cases, to suffer hallucinations or paralysing physical collapses called cataplexy. Sweden was not alone in facing narcolepsy cases after the jab drive. In Finland, 79 children aged 4 to 19 developed narcolepsy after receiving the Pandemrix vaccine in 2009 and 2010, while in Sweden, the number was close to 200, according to figures in the 2 countries released last year [2012]. Sweden has more than 9 million citizens, while Finland has some 5 million, making the cases approximately proportionate to population size. In the past years, the Finnish and Swedish governments have both agreed to provide financial compensation for the affected children after their own national research showed a link between the inoculation and narcolepsy.

Primary Aldosteronism:a Potassium channelopathy?

Endocrinology. 2013 Nov 18. [Epub ahead of print] Minireview: Potassium Channels and Aldosterone Dysregulation. Is Primary Aldosteronism a Potassium Channelopathy? Gomez-Sanchez Celso E,(Univ.MISSISSIPPI,JACKSON) Oki K. Primary aldosteronism is the most common form of secondary hypertension and has significant cardiovascular consequences. Aldosterone-producing adenomas (APAs) are responsible for half the cases of primary aldosteronism, and about half have mutations of the G protein-activated inward rectifying potassium channel Kir3.4. Under basal conditions, the adrenal zona glomerulosa cells are hyperpolarized with negative resting potentials determined by membrane permeability to K+ mediated through various K+ channels, including the leak K+ channels TASK-1, TASK-3, and TREK1, and G protein inward rectifying potassium channel Kir3.4. Angiotensin II decreases the activity of the leak K+ channels and Kir3.4 channel and decreases the expression of the Kir3.4 channel, resulting in membrane depolarization, increased intracellular calcium, calcium-calmodulin pathway activation, and increased expression of CYP11B2, the last enzyme for aldosterone production. Somatic mutations of the selectivity filter of the Kir3.4 channel in APA results in loss of selectivity for K+ and entry of sodium, resulting in membrane depolarization, calcium mobilization, increased CYP11B2 expression, and hyperaldosteronism. Germ cell mutations cause familial hyperaldosteronism type 3, which is associated with adrenal zona glomerulosa hyperplasia, rather than adenoma. Less commonly, somatic mutations of the sodium-potassium ATPase, calcium ATPase, or the calcium channel Cav1.3 have been found in some APAs. The regulation of aldosterone secretion is exerted to a significant degree by activation of membrane K+ and calcium channels or pumps, so it is not surprising that the known causes of disorders of aldosterone secretion in APA have been channelopathies, which activate mechanisms that increase aldosterone synthesis. PMID: 24248457 [PubMed - as supplied by publisher]

UK NEW STATESMAN: FEMALE GENITAL MUTILATION

Syndicate contentRSS A London clinic fighting back against female genital mutilation By Natasha Tsangarides Published 21 December 2013 10:17 The West London clinic offers a vital service for FGM survivors. Maryam has just had “reversal” surgery, a procedure to open up the vagina, which had been sewn up during FGM. “It’s amazing, I didn’t realize I wouldn’t feel pain,” she said. “My legs were shaking from fear but I didn’t feel a thing.” Maryam was 10-years-old when she was “cut” in Somalia. “I remember the day,” she recalled. “My mum sent me to the shop to get a needle and thread. I knew what was going on. The old lady had already done it to girls on my street that day. I felt ashamed if I didn’t do it. “Recently I got married. I suffered with sex. There’s no reason for my vagina to be closed. My husband is Somali so he expected I would be cut. When my husband realised I was closed though, he was disappointed. He said, ‘You’d better open this up’. He’s going to be happy now.” The West London African Women’s Community Clinic, based at Charing Cross hospital, runs an FGM service every Wednesday afternoon. The clinic is a pioneering centre set up in 2010 to deliver services for women suffering the consequences of FGM. Treating women mostly from the Somali community, the clinic is breaking the taboo surrounding the procedure. This November, several campaigns have been launched nationally in order to raise awareness and eliminate the practice of FGM in the UK. What is the scale of the problem and who is affected by it? What are the health consequences for victims of FGM? With the practice happening behind closed doors, can it really be eliminated in the UK? FGM involves cutting female genital organs for non-medical reasons. In the UK, over 20,000 girls are at risk and 66,000 women are living with the consequences of FGM, according to a study carried out by the anti-FGM charity, Forward. A cultural practice, FGM developed to preserve women’s virginity and control sexuality. It is prevalent in 28 countries in Africa and in parts of Asia and the Middle East. 97% of women in Somalia undergo the horrific procedure, typically between the ages of 5 and 9 years old, according to a 2007 study by the London School of Hygiene and Tropical Medicine. The study estimated that 15,272 Somali women aged between 15 and 49 are living with FGM in England and Wales. Somalis comprise one of the largest ethnic groups in Hammersmith and Fulham. The 2011 census shows that 45% of the population in White City is foreign-born. The majority (636 people) come from Somalia, of which just over half are women. With the practice so ingrained in Somali culture, migration to the UK has not stamped it out. Some second-generation girls born in the UK are being sent back to their parent’s countries of origin or, probably less commonly, having the procedure done here. Freedom of Information requests submitted by the Evening Standard show that 2,115 FGM patients were seen at London hospitals between 2010 and summer this year. The West London African Women’s Service provides gynaecology, maternity and sexual health care for women who have undergone FGM. It is delivered at two sites: at Chelsea and Westminster Hospital as well as the community clinic at the West London Centre for Sexual Health, Charing Cross Hospital. Between June 2011 and August 2013, 662 women with FGM have accessed the service, of whom 432 attended the community clinic. The impact of the service has not gone unnoticed. In 2012, it won two all-party parliamentary maternity awards for most marked improvement in a service to address health inequalities and the best example of a service to address complex needs, and this year it also won the accolade of ‘Adult Sexual Health Service of the Year’ by the UK Sexual Health Awards. Sagal Osman, an anti-FGM campaigner from White City, helps local West London women access the clinic. Originally from Somalia and a survivor of FGM, Sagal developed relationships with practitioners at Charing Cross hospital and secured regular clinics for FGM patients at the West London African Women’s Community Clinic. Sagal said: “At the moment I have five new patients every week and I have a waiting list of about 50 people. Most patients are Somalis. It’s probably the hardest community to reach. But over the years trust has been built.” Women come to the clinic for a variety of reasons, typically stemming from the long-term consequences associated with FGM. These include recurrent urinary infections, painful scarring, severe menstrual cramps, wound infections, fertility problems, complications in pregnancy and even renal impairment or failure. Dr Naomi Low-Beer, Consultant Gynaecologist at Chelsea and Westminster Hospital, and lead doctor for the FGM service at the West London clinic, performs the invaluable reversal surgery. She explained: “With the most severe type of FGM, the clitoris and labia have been totally removed, the vaginal opening closed, with a tiny passage left for urine and menstrual blood. This makes sex painful or impossible. “Women with this type of FGM do benefit from surgery. It is often referred to as ‘reversal’, but rather than reversing the FGM the surgery opens the vagina so that women can have sex without pain. Otherwise, it can take months and months of painful attempts at penetration. A number of women come in to have the surgery pre-marriage or before their first relationship, and others come because they are suffering from repeated urine and vaginal infections or very painful periods. The surgery can help women with these problems too. It can be safely performed under local anaesthetic in the outpatient clinic. In offering this service, you feel like you’re making a difference.” Naomi works closely with an all-female team of committed specialists, including an obstetrician, FGM specialist midwife, doctors specialising in HIV and Sexual Health, and of course Sagal Osman, anti-FGM campaigner and health advocate. Between them they provide comprehensive specialist care for women with FGM. Between June 2011 and August 2013, of the 662 women attending the West London African Women’s Service 69 women had de-infibulations, otherwise known as reversal surgery, of whom 37 had this performed at the West London clinic. Alia*, draped head-to-foot in black, sits nervously in the clinic’s waiting room. Having had reversal surgery four weeks ago, she is at the clinic to treat syphilis and Hepatitis B, infections commonly attributed to dirty tools used during FGM. Despite having the infections, Alia is optimistic following the successful surgery. She says, “I feel better and I feel like my life has changed.” Tending to the needs of women suffering the after-effects of FGM is only one part of the problem. Preventing it from happening is something campaigners, frontline workers and the government have been battling with for almost thirty years. In July this year, Hammersmith and Fulham Council passed a special motion that proposes to raise awareness and end all forms of FGM in the borough. Councillor Helen Binmore said: “We have just set up a strategic board and hope that our coordinated multi-agency approach will help improve how agencies, services and professionals respond to this issue and offer protection to women and girls from FGM.” Efua Dorkenoo OBE is Advocacy Director at Equality Now, an international human rights organisation. She said: “Parents know about the health consequences but it still goes on. Parents need to know that professionals are keeping an eye on their children and that they will report FGM happening and that there can be prosecutions.” FGM has been a criminal offence since 1985 and the 2003 Female Genital Mutilation Act made it illegal for British citizens and permanent residents to practice FGM within and outside the UK. To date, there have been no prosecutions. By comparison, France has convicted around 100 parents and practitioners. Misplaced cultural sensitivities, a failure to see FGM as a child protection issue and a lack of accountability have so far impeded successful prosecutions taking place, Mrs Dorkenoo said. “The issue needs to be brought into the mainstream as a child abuse issue through a combination of education, protection and prosecutions.” Momentum is growing in the campaign to raise awareness and eliminate FGM with the government making it a national priority. Last month, the London Metropolitan Police have, for the first time, arrested two people suspected of performing FGM on a five-week old girl. The case is under investigation and a successful prosecution would be a landmark victory and an important step to achieving the goal of eliminating FGM.

INDIA : increased incidence MYCOBACTERIUM LEPRAE

LEPROSY - INDIA (05): (ANDHRA PRADESH) INCREASED INCIDENCE ********************************************************** A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: Sat 21 Dec 2013 Source: The Times of India Times News Network (TNN) [edited] Leprosy is increasing alarmingly in Andhra Pradesh with the government doing little to check the bacterial infection from spreading, experts said as a staggering 8285 cases were reported in the state during 2012-13. As many as 239 new cases were detected in Hyderabad in the same period. Health department officials said Andhra Pradesh now figures among the top 12 states with the highest caseloads of leprosy in the country. The proportion of new paediatric cases in the state was also among the highest in the country, experts said. Data from the National Leprosy Eradication Programme shows that out of the total new cases, a substantial 911 cases (11.34 per cent) are of children, officials said. Experts said the numbers have gone up particularly in the last 2 years. During 2011-12, 7820 cases were detected, they pointed out and attributed the situation to the state government's apathy towards the health issue, so much so that it is now regaining ground. "We could not identify these cases well in time," said Dr Michael Sukumar, a WHO consultant who is working with the state leprosy cell [in Hyderabad], underscoring a situation when agencies are sometimes helpless when local governments fail to read health warnings.

SWITZERLAND:PRESERATIVE-FREE EYE DROPS.

Consider using preservative-free topical medication in patients with ocular surface disease Publishing date: December 2013 The Science behind the Tip Many glaucoma drops contain a preservative agent to minimise the risk of microbial contamination. Benzalconium chloride, a cationic surfactant, is the most widely used preservative, but even in doses of 0.002% to 0.004% can result in toxic effects on the surface of the eye and ocular inflammation. (1) Symptoms and signs of ocular surface disease (OSD) are found in 48-60% of patients on topical glaucoma medication (2) (3). This is a multifactorial condition which leads to adverse local reactions, reduced visual acuity, reduced quality of life and reduced compliance with prescribed therapy. (1). Risk factors associated with OSD include the number of preserved drops used and duration of therapy. (4) An improvement of symptoms is found if these patients are switched to preservative-free topical medication. (1) Contributor: Frances Meier-Gibbons, Switzerland References 1. Baudouin C, Labbé A, Liang H et al Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res 2010; 29 (4) 312-334. 2. Leung EW, Medeiros FA, Weinreb RN. Prevalance of ocular surface disease in glaucoma patients. J Glaucoma 2008; 17 (5) 350-355. 3. Fechtner RD, Godfrey DG, Budenz D et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure lowering medications. Cornea 2010;? 29: 618-621. 4. Rossi GC, Pasinetti GM, Scudeller L et al. Risk factors to develop ocular surface disease in treated glaucoma or ocular hypertension patients. Eur J Ophthalmol 2013; 23 (3) 296-302. Tip Editors: John Salmon and John Thygesen Reviewers: Roger Hitchings and Anders Heijl

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