An article published in The Lancet today reports that apixaban is a more convenient and effective anticoagulant than enoxaparin. It is better at preventing venous thromboembolism after knee replacement surgery. Also, apixaban does not increase the risk of bleeding. This is an essential concern with anticoagulants since this can hinder recovery and predispose patients to infections that could damage the prosthesis.

Presently, the existing prophylactics such as heparins (like enoxaparin) or other drugs (such as fondaparinux) need regular injections. Furthermore, the use of warfarin has various disadvantages in routine practice, and mechanical methods are burdensome.

Michael Rud Lassen, Department of Orthopaedics, Horsholm Hospital, University of Copenhagen, Denmark, and colleagues investigated to determine whether apixaban would be better than enoxaparin in both keeping thromboembolism and bleeding to a minimum. They undertook a randomized controlled phase 3 trial. The patients either received 2.5 mg of apixaban twice daily or 40 mg enoxaparin once daily. The primary outcome was a composite of deep vein thrombosis, non-fatal pulmonary embolism, and death from any cause.

A total of 147 patients (15 percent of 976) on apixaban and 243 (24 percent of 997) on enoxaparin had a primary outcome event. This showed a statistically significant difference. There was no noteworthy disparity between the groups in the bleeding during treatment.

The authors explain: “2•5 mg apixaban twice daily, starting on the morning after total knee replacement, offers a convenient and more effective orally administered alternative to 40 mg per day enoxaparin, without increased bleeding.”

They say in closing: “These favourable results might help surgeons to resolve their clinical dilemma when considering anticoagulant prophylaxis for total knee replacement. Bleeding can delay recovery and can predispose to infections that endanger the prosthesis. The small but occasionally important increase in surgical bleeding that is attributed to enoxaparin can contribute to underuse of effective prophylaxis.”

In an associated note, Dr Jawed Fareed, Department of Pathology, Loyola University Medical Center, Maywood, IL, USA, and Dr Russell Hull, University of Calgary, Calgary, Canada comment: “we are potentially a step closer to the unmet need of oral antithrombotic therapy without need for monitoring.”

They write in conclude: “The ideal prophylactic drug would reduce the frequency of postoperative venous thromboembolism without causing bleeding and other complications in patients postoperatively. An ideal drug does not yet exist. The balance is fairly simple: a stronger anticoagulant effect is associated with fewer thrombotic events, but with a cost of increased occurrence of bleeding.”

“Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomized double-blind trial”

Older patients with acute myeloid leukemia (AML) might benefit from a drug that reactivates genes that cancer cells turn off, according to research at Washington University School of Medicine in St. Louis and collaborating institutions. The researchers say the findings support further investigation of the drug, decitabine, as a first-line treatment for these patients, who have limited treatment options.

Almost two-thirds of AML patients over age 65 do not receive treatment for the disease because standard therapy can be risky and often is ineffective. On average, such patients survive only 1.7 months after diagnosis.

“Older leukemia patients don’t have good treatment options because the chemotherapy and stem cell transplants that we commonly use for younger patients are often too toxic for them,” says lead author Amanda F. Cashen, M.D., assistant professor of medicine in the Division of Oncology and a bone marrow transplant specialist with the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

“Furthermore, the biology of acute leukemia in the older patient population is different, making their response rate lower, their risk of relapse higher and their cure rates lower,” she says. “So we definitely need new therapies in that patient population – treatments that are going to be both better tolerated and more effective.”

The study, to be published in an upcoming issue of the Journal of Clinical Oncology and now available on-line, was conducted at three sites: Washington University School of Medicine; the University of California, Los Angeles; and the City of Hope National Medical Center in Duarte, Calif. The researchers tested decitabine in 55 AML patients with an average age of 74 years.

Decitabine can increase the activity of genes that have been silenced in cancer cells. It works by reducing the amount of DNA that is marked with a chemical tag called a methyl group. Scientists think that the excess methylation found in cancer cells inactivates genes that normally suppress tumor development.

All patients received the same decitabine dose for five consecutive days every four weeks until their disease stopped responding to the drug and began progressing or until an adverse event occurred to prevent further participation. By comparison to standard chemotherapy and stem cell transplantation, the treatment was considered a low-intensity treatment and was more tolerable for elderly patients, especially those with accompanying medical problems.

In 24 percent of the study participants, blood counts and bone marrow returned to normal, which is considered a complete response. It took 4.5 cycles of decitabine treatment on average to achieve a complete response. In those with a complete response, average survival time was 14 months. For all study participants, average survival time was 7.7 months.

Treatment-related adverse events included low blood counts (red cells, white cells and platelets), infection, fever and fatigue. Almost half of the study participants had at least one serious adverse event. Seven patients discontinued treatment, and three patients died as the result of adverse events.

“We have to wait for the results of further trials of decitabine to have a better estimate of the response rate and survival outcome compared to other low intensity options for older adults,” Cashen says. “This study can’t definitively establish decitabine’s role for treating older adults with AML, but it certainly excites us to study it more.”

Small amounts of lead in the bodies of healthy children and teens amounts well below the levels defined as “concerning” by the U.S. Centers for Disease Control and Prevention (CDC) may worsen kidney function, according to a Johns Hopkins Children’s Center study published in the Jan. 11 issue of Archives of Internal Medicine.

In 1991, the CDC reduced the lead level “of concern” for children from 30 micrograms to 10 micrograms per deciliter of blood, but the Johns Hopkins findings suggest that even levels below 10 present a health risk, providing the first evidence that lead levels that low may impair kidney function.

“To our knowledge, this is the first study to show that very low levels of lead may impact kidney function in healthy children, which underscores the need to minimize sources of lead exposure,” says lead investigator Jeffrey Fadrowski, M.D. M.H.S., a pediatric nephrologist at Hopkins Children’s.

The Johns Hopkins team cautions that their findings present only a snapshot of kidney status and lead levels, and do not offer definitive proof of cause and effect between the two. But the scientists say their findings are worrisome and emphasize the urgent need for studies that track lead levels and kidney function over time to better understand the interplay between the two.

“Our findings were particularly striking because we saw slightly decreased kidney function in healthy children without conditions that could account for it, and this could spell more kidney trouble down the road as these children get older or if they acquire additional risk factors for kidney disease, such as high blood pressure and diabetes,” says Susan Furth, M.D. Ph.D., senior investigator on the study and a pediatric nephrologist at Hopkins Children’s.

Of the 769 healthy children and teens in the study, ages 12 to 20, more than 99 percent had lead levels below 10, with an average level of 1.5 micrograms per deciliter. Those with lead levels in the upper quarter of the normal range appeared to have worse kidney function than children with lower lead levels. Kidney function is defined by the speed with which the kidneys filter the blood. Those with lead levels above 2.9 had a kidney filtration rate 6.6 units (milliliters of blood filtered per minute and adjusted for body size) lower than children whose lead levels were below 1 microgram per deciliter. Researchers also found that for each twofold increase in the amount of lead in the blood, the kidney’s filtration capacity dropped by 2.3 units in males and by 3.3 in females. The link between higher lead levels and worse kidney function persisted even after investigators eliminated high blood pressure less than 5 percent of those in the study had it as a possible factor affecting kidney status.

In the current study, the investigators measured kidney function by estimating the kidneys’ filtering capacity, called glomerular filtration rate (GFR), using two tests: a standard creatinine test, which measures the speed with which the kidneys filter out creatinine from the blood, and a newer test that measures how fast the kidneys filter out the protein cystatin C. Cystatin C is believed to be a more accurate gauge because, unlike creatinine, which can fluctuate depending on muscle mass and other factors, its levels are more stable. Indeed, the differences in kidney function were far more pronounced when the researchers looked at cystatin C and not as significant when they applied the standard creatinine test. The investigators say this could mean that past studies that have used creatinine tests may have underestimated the true effect of lead on kidney function.

Lead exposure is a well-established risk factor for neurological damage and developmental delays in children, while chronic exposure to high lead levels is a well-known cause of chronic kidney disease in adults. Despite the elimination of lead from gasoline and paint, most Americans still have detectable lead levels in the blood. The mean blood lead levels in the 12-to-19-year-olds were 1.5 micrograms per deciliter in 1991 to 1994 and 1.1 micrograms per deciliter from 1999 to 2000, researchers say.

Scientists have found four new regions of the genome that increase the risk of a common blood cancer, according to results published in the journal Nature Genetics.

Professor Richard Houlston and his team at The Institute of Cancer Research (ICR) have now found the location of 10 genetic variants, common in the European population, that are associated with an increased risk of chronic lymphocytic leukaemia (CLL).

Professor Houlston’s team last year proved that people’s genes could make them more susceptible to CLL, identifying six regions of the genome more common among sufferers. In the latest paper, also funded by the charity Leukaemia Research, his team have identified another four regions that influence an individual’s risk of CLL.

CLL is the most common form of leukaemia in western countries, with around 2,700 people in the UK diagnosed each year with the disease, most after age 55.

The genetic factors identified in the latest study are all common in the population, and each increases the risk of CLL by between 1.2 and 1.4-fold. Each person may carry from a few of the identified risk factors to all the risk factors. Importantly, the more genetic factors carried, the higher their risk of developing CLL.

“People who have more than 13 risk factors are seven times more likely than the general population to develop CLL,” Professor Houlston says.

The risk factors were identified using a genome wide association study, a technique that ICR scientists have used previously to find risk genes in breast, prostate, testis, brain and colon cancer and childhood leukaemia. They scanned the genome of 2,503 CLL patients and compared them to 5,789 healthy individuals, looking for single letter differences in DNA between the two groups.

The study confirmed that the inherited risk of CLL is not due to a single gene, but often as a result of the cumulative effect of many genetic changes with small effects. The study found that 87 per cent of people with CLL would have at least one of these genetic factors.

The locations of these factors also provides new insights into the mechanism by which leukaemia develops.

Dr David Grant, Scientific Director of Leukaemia Research, says, “The possibility that this form of leukaemia may run in families has been suspected for sometime. So it is pleasing that this research is providing the genetic evidence that an increased risk of developing CLL can be inherited. However it is clearly a complex picture and we need to study more families before we can be certain of the particular genetic traits that are most important.”

A new study conducted at Ben-Gurion University of the Negev (BGU) reveals that Celebrex and other anti-inflammatory coxib medications may counter the positive effects of aspirin in preventing blood clots.

The research, published in the Proceedings of the National Academy of Sciences (PNAS), indicates that people who are taking aspirin and coxibs together are in fact inhibiting the aspirin’s effectiveness in preventing heart attacks and strokes.

“This finding strongly suggests that humans who are consuming coxibs and a low dose of aspirin simultaneously are exposed to a greater risk of cardiovascular events,” said Professor Gilad Rimon, Department of Clinical Pharmacology, Ben-Gurion University of the Negev in Israel.

In the past decade, a new group of anti-inflammatory drugs, coxibs, which include Celebrex and Arcoxia was developed to treat arthritis as well as other pain. Arthritis patients who take Celebrex are instructed to take low-dose aspirin to counteract Celebrex’s own potential clot-promoting effect.

Aspirin is the oldest and one of the most effective non steroidal anti-inflammatory drugs. It is also well known for its ability to prevent the blood clots that can potentially lead to heart attack and stroke. Therefore, doctors often advise patients who are more prone to heart-related illnesses to take a daily tablet of low dose aspirin (81 mg). Approximately, 50 million Americans take aspirin every day to reduce their risk of cardiovascular diseases.

Now, the BGU research suggests that in the presence of coxibs, asprin’s protective role in preventing new blood clots is blunted.

This finding mirrors a cooperative study conducted at the University of Michigan, Ann Arbor that showed for the first time that Celebrex and other coxibs directly interfere with the protective qualities of aspirin.

An international study authored by a UT Southwestern Medical Center researcher has concluded that the anemia drug darbepoetin alfa works no better than a placebo in several other applications previously thought to be promising.

Darbepoetin alfa is one of a class of drugs used to increase red blood cells in patients with type 2 diabetes, chronic kidney disease and anemia, but in a study of 4,038 patients, it did little to reduce cardiovascular problems, death or even the need for dialysis.

Patients have used the drug and other similar drugs for at least a decade to improve the symptoms of anemia.

“We were disappointed that the drug didn’t make a difference,” said Dr. Robert Toto, professor of internal medicine at UT Southwestern and senior author of the study in The New England Journal of Medicine. “We set out doing this trial to prove whether treatment of anemia would help our patients.”

Researchers also found that subjects who took the drug were nearly twice as likely to have a stroke as those who received a placebo – 101 subjects compared with 53.

“This is a surprise,” Dr. Toto said. “Clinicians should not expect that treatment of anemia with darbepoetin and other drugs in its class will reduce their risk of cardiovascular events or prevent their kidney disease from progressing. If a clinician is treating a patient for fatigue and other symptoms of anemia and the symptoms do not improve, they should consider stopping the drug, because it may expose the patient to increased risk of stroke.”

Chronic kidney disease, type 2 diabetes and anemia affect about 1 million people in the U.S., he said. Drugs such as darbepoetin alfa for treating anemic patients on dialysis (in the final stage of kidney disease) were approved in the late 1980s. Soon afterward, accepted guidelines suggested using the drug with chronic kidney disease patients not on dialysis in hopes of improving symptoms, cardiovascular death rates and preventing chronic kidney disease from progressing to dialysis.

While studies were done in an attempt to determine optimal hemoglobin levels using such drugs in these patients, no trial was conducted comparing the drug with a placebo, until TREAT ” Trial to Reduce Cardiovascular Events with Aranesp Therapy.

“From a scientific perspective, TREAT is the most rigorous,” Dr. Toto said. “It’s a randomized, double-blind, placebo-controlled trial.”

US scientists have developed synthetic red blood cells that mimic the softness, flexibility and oxygen carrying-property of natural red blood cells, and can be used to deliver drugs and diagnostic agents.

The researchers behind the development are from the University of California, Santa Barbara (UCSB) and the University of Michigan and have published a paper about it in the 22 December print issue of the Proceedings of the National Academy of Sciences.

They write in their background information that while synthetic carriers have brought many advances in drug delivery, they don’t match the sophistication of natural biological materials such as red blood cells (RBCs).

RBCs are the most prolific type of cell in human blood, and are highly specialized: they have a unique shape, size and composition and they are mechanically flexible, properties that optimize them for “extraordinary biological performance”.

The primary role of natural red blood cells is to carry oxygen, and the researchers reported that the new synthetic red blood cells (sRBCs) do that very well, retaining 90 per cent of their oxygen-binding capacity after a week.

However, the sRBCs also “deliver therapeutic drugs effectively and with controlled release”, and “carry well-distributed contrast agents for enhanced resolution in diagnostic imaging”, according to a recent press release from UCSB.

Co-author Dr Samir Mitragotri, who is professor of chemical engineering at UCSB and leader of the research group working on drug delivery synthetic materials, told the media that:

“This ability to create flexible biomimetic carriers for therapeutic and diagnostic agents really opens up a whole new realm of possibilities in drug delivery and similar applications.”

“We know that we can further engineer sRBCs to carry additional therapeutic agents, both encapsulated in the sRBC and on its surface,” he added.

For the study, Mitragotri and colleagues synthesized the particles by making polymer templates shaped like tiny doughnuts, coating them with up to nine layers of hemoglobin and other proteins, then removing the core templates, leaving particles of the same size (about 5 microns in diameter), shape and flexibility, and able to carry as much oxygen, as natural red blood cells.

However, it is their flexibility that makes these new sRBCs stand apart from “conventional” polymer-based biomaterials developed as carriers for therapeutic and diagnostic agents, said the researchers. This enhanced flexibility means the sRBCs can enter and flow through channels that are smaller than their resting diameter, stretch in response to flow, and become disc-shaped again when they exit, just like natural RBCs.

The researchers said that the techniques they use to make sRBCs could also be used to make particles that mimic the shape and function of diseased cells, such as those that occur in inherited blood disorders like sickle-cell anemia and hereditary elliptocytosis, and thus aid the understanding of these diseases.

The mouse is a standard laboratory model organism, but there are currently few resources that describe conventional techniques to analyze blood and blood-forming tissues in this species. A newly released set of compact and easy-to-use laboratory resources from Cold Spring Harbor Laboratory Press fills this gap. Mouse Hematology features step-by-step protocols for the preparation, enumeration, and microscopic examination of peripheral blood, bone marrow, and other hematopoietic tissues in the mouse. The laboratory manual is accompanied by a DVD with video demonstrations of the techniques and a poster of blood cell types for easy identification at the microscope.

Mouse Hematology was written by James J. Lee (Mayo Clinic Arizona) and two members of his lab, Michael P. McGarry and Cheryl A. Protheroe. All three have extensive experience employing hematological procedures in mice, and they wrote the book partly in response to numerous requests for help in preparing samples and identifying blood cell types. “Our goal here is to present standards and procedures for the examination of blood and blood-forming tissues of the laboratory mouse,” the authors write in the preface of the book. “The described methodologies will allow for the morphological examination of blood, bone marrow, and/or hematopoietic tissues in research protocols and, in turn, will provide a greater understanding of mouse models of human disease.”

The manual describes how to collect blood samples from adult mice and mouse pups; determine hematocrit and use a hemocytometer to count cells; and smear, fix, and stain blood films. Detailed protocols for performing bone marrow biopsies and for preparing bone marrow smears and suspensions for cytospin analysis are also provided. High-quality video demonstrations of most of the techniques are included on the DVD.

In addition to protocols, Mouse Hematology contains full-color images and detailed descriptions of the morphology of mature blood cells and their progenitors. The poster also presents examples of different blood cell types and will be a useful reference at the microscope.

This set of resources will be useful to laboratory scientists at all levels who work with mice to study hematopoiesis, stem cells, the immune system, and genetic diseases that affect the blood.

Scientists at VIB and Ghent University in Flanders, Belgium have found an unexpected ally for the treatment of septic shock, the major cause of death in intensive care units. By inducing the release of nitric oxide (NO) gas in mice with septic shock, researchers Anje Cauwels and Peter Brouckaert discovered that the animal’s organs showed much less damage, while their chances of survival increased significantly. That’s contrary to all expectations, since it is generally assumed that nitric oxide is responsible for the potentially lethal drop in blood pressure in septic shock.

Septic shock, or sepsis, is a medical condition in which acute inflammation, low blood pressure, and blood clotting cause a dangerous decrease in the delivery of blood to the organs. Because of the lack of oxygen, the patient’s organs start to fail, one after the other. Currently, only supportive treatment is available.

It is generally assumed that nitric oxide (NO) gas is responsible for the hypotension and cardiovascular collapse in septic shock. Therefore, a lot of medical research is focused on combating NO, which is also a messenger molecule in the body. Attempts to inhibit its production paradoxically led to a worsening of the organ damage and in an increased lethality, both in animal models and in a clinical trial in sepsis patients. This led to the assumption that NO also has positive effects in sepsis, but up to now NO remained a prime suspect for the pathogenesis of the cardiovascular shock.

The team in Ghent is turning this paradigm upside-down in an article that will appear in The Journal of Experimental Medicine on Monday 21 December 2009. During their research, Cauwels and Brouckaert administered nitrite – a substance that releases NO – to mice with septic shock. The nitrite treatment, in sharp contrast with the worsening effect of inhibiting NO-synthesis, significantly attenuates hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction, and mortality in mice. It is not yet known what mechanisms are at work behind this observation. That will be the subject of further research.

For now, not only is this discovery revolutionizing the way in which scientists view nitric oxide’s role in septic shock – it also opens possibilities for treatment. Instead of trying to prevent the effects of NO, they should rather be imitated or reinforced to provide a solution for saving organs or particular parts of the body where there is a lack of oxygen due to septic shock.

Polyphosphate from blood platelets plays a key role in inflammation and the formation of blood clots, scientists from the Swedish medical university Karolinska Institutet have shown. The study, which is presented in the prestigious scientific journal Cell, describes how this mechanism can be used in treatment.

Blood clots are a common cause of myocardial infarction and stroke, and they arise when blood coagulates and clogs a blood vessel. Scientists have shown that the formation of a blood clot involves the aggregation of blood platelets and the formation of structures known as “fibrin threads”, in combination with inflammation in the blood vessel. The molecular processes behind this, however, are only partially known.

A research group at Karolinska Institutet, in collaboration with American and European scientists, has discovered that an inorganic polymer, polyphosphate, plays a key role in both inflammation and the formation of blood clots. Experiments on mice and with patient plasma have shown that polyphosphate is released by blood platelets and activates Factor XII, a protein that scientists have previously shown to contribute to coagulation. Polyphosphate also activates inflammatory substances that contribute to leakage from the blood vessel, which is a characteristic feature of inflammation.

The scientists show also that certain enzymes, phosphatases, that break down polyphosphate can prevent both inflammation and the formation of blood clots in the blood vessels of mice. Thus the scientists believe that phosphatases can become the focus for a new type of treatment for blood clots and inflammation.