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March - WHAT'S NEW IN COAGULATION?

SMFM 2009: Checklist Useful for Identifying Venous Thromboembolism Risk in Pregnant Womenhttp://www.medscape.com/viewarticle/587740
The first study was a retrospective analysis of 17,325 deliveries over a 3-year period at Albert Einstein Medical Center/Montefiore Hospital. In all, there were 19 antepartum cases and 22 postpartum cases of VTE, for a total incidence of 2.4 in 1000 deliveries. An Obstetrical VTE Risk Factor Assessment checklist was developed from risk factors listed by the Royal College of Obstetricians and Gynaecologists, and calculated, using the risk factors identified in patients' charts, how the women in their analysis would have scored. Each factor was weighted according to its severity. For example, a history of DVT or pulmonary embolism was given 3 points, cesarean delivery was given 2 points, and being older than 35 years was given 1 point. A total score of less than 3 was considered low risk; a score of 3 or more was deemed high risk. Based on this system, 27 of 41 patients would have been identified as at-risk, but only 15 women (56%) received any type of prophylaxis, and only 3 of those (11%) received pharmacoprophylaxis.
A second group of investigators found that maternal DVT does not necessarily mean poor perinatal outcomes. A population-based study of 211,964 deliveries occurring over 20 years A total of 122 of the pregnant women (0.06%) had a history of DVT. On multiple logistic regression analysis, maternal age (P = .004), chronic hypertension (P = .005), and previous cesarean delivery (P < .001) were the most significant risk factors for DVT. DVT itself was an independent risk factor for premature delivery, with an odds ratio of 1.75 (P = .033). Other significant risk factors for prematurity were maternal age, pregestational diabetes, hypertensive disorders, and multiple gestations.
However, there were no significant differences in Apgar scores or in the incidence of perinatal mortality or congenital malformations between children born to women with DVT and those born to women without DVT. The authors concluded that, although DVT is a risk factor for spontaneous preterm delivery, it does not appear to raise the risk for adverse perinatal outcomes.
Society for Maternal-Fetal Medicine (SMFM) 29th Annual Meeting: Abstracts 535 and 499. Both abstracts January 30, 2009.

FDA NEWS

FDA Approves Orphan Drug ATryn to Treat Rare Clotting Disorder
The U.S. Food and Drug Administration today issued its first approval for a biological product produced by genetically engineered (GE) animals.
The approval is for ATryn, an anticoagulant used for the prevention of blood clots in patients with a rare disease known as hereditary antithrombin (AT) deficiency. These patients are at high risk of blood clots during medical interventions, such as surgery, and before, during and after childbirth. ATryn is a therapeutic protein derived from the milk of goats that have been genetically engineered by introducing a segment of DNA into their genes (called a recombinant DNA or rDNA construct) with instructions for the goat to produce human antithrombin in its milk. Antithrombin is a protein that naturally occurs in healthy individual and helps to keep blood from clotting in the veins and arteries.
Because hereditary AT deficiency occurs in a small population (approximately 1 in 5,000 people in the United States), the FDA granted ATryn an orphan drug designation. The orphan drug designation system encourages the development of medications for patients with a rare disease or condition.
The agency held an advisory committee meeting in January to seek the opinion of outside experts, who agreed that ATryn is safe and effective. CVM also briefed the committee about the animal drug components of the application. Hereditary AT deficiency generally is first recognized and diagnosed in teenagers or young adults when they develop clots in their blood vessels, particularly during pregnancy, surgery, or prolonged bed rest.
CBER evaluated two studies that included 31 patients with hereditary AT deficiency who received ATryn to prevent thromboemboli (TE) before, during or after surgery or childbirth. All but one patient had a prior history of at least one TE, which are likely to recur in high-risk situations if left untreated. Only one of the 31 patients treated with ATryn developed a TE. The most common adverse reactions reported were hemorrhage and reactions at the infusion site. These reactions occurred in approximately five percent of patients.
As part of its review of the GE goat, CVM assessed the safety of the rDNA construct to the animals, including a full review of the construct and its stability in the genome of the goats over seven generations. No adverse outcomes were noted. CVM reviewed and concurred with the sponsor's plan to continue to monitor the construct and its expression for the lifetime of the approved product.
A summary of the information on which the FDA made its approval decision for the rDNA construct in the goats, and CVM's guidance on the regulation of GE animals containing heritable rDNA constructs are available at http://www.fda.gov/cvm/GEAnimals.htm .

1.0 FDA NEWS
FDA Approves RiaSTAP for Treatment of Bleeding in Patients with Rare Genetic Defect
The U.S. Food and Drug Administration today licensed RiaSTAP, an orphan drug for the treatment of bleeding in patients with a rare genetic defect known as congenital fibrinogen deficiency. Without treatment, these patients are at risk of potentially life-threatening bleeding.
People with congenital fibrinogen deficiency are unable to make sufficient amounts of fibrinogen, which plays an important role in blood coagulation by helping to form blood clots and prevent bleeding. Fibrinogen is manufactured in the liver and circulates in the blood plasma in a normal concentration of 250-400 mg/dL.
Fibrinogen deficiency affects only 150 to 300 people in the United States and is usually diagnosed at birth when newborns bleed from their umbilical cord site. Children with the defect need to curtail activities because of risk of bleeding from minor trauma.
RiaSTAP is an intravenous fibrinogen concentrate made from the plasma of healthy human blood donors. The product is indicated for patients who have no fibrinogen or low levels of the substance, an abnormality known as afibrinogenemia, or for those patients whose fibrinogen levels are below 50 mg/dL, an abnormality known as hypofibrinogenemia. The product is not indicated for patients with dysfibrinogenemia, who may have normal fibrinogen levels but defective fibrinogen function. Patients such as these are at risk for both bleeding and clotting complications.
The licensing of RiaSTAP was supported by a study of 15 patients with afibrinogenemia who achieved the target level of fibrinogen expected to prevent bleeding after they received 70 mg/kg of the drug. In addition, plasma from 14 of the 15 patients showed increased maximum clot firmness, a surrogate marker likely to predict clinical benefit. Fever and headache were the most common adverse reactions.Clinical benefit will be further verified in a postmarketing study which will include both afibrinogenemic and hypofibrinogenemic patients.
Orphan drugs are drugs or biologics intended for use in a rare disease or condition. Manufacturers are qualified to receive certain government benefits in exchange for developing such products. RiaSTAP Fibrinogen Concentrate (Human)] was developed under the FDA's accelerated approval regulations.

FDA Continues to Investigate Bleeding Risk for Xigrishttp://www.medscape.com/viewarticle/587847

The US Food and Drug Administration (FDA) announced today in an early communication that it is continuing to evaluate the incidence of serious bleeding events and death in patients who received drotrecogin alfa activated (Xigris, Eli Lilly and Co), a recombinant human activated protein C indicated for the treatment of severe sepsis. The FDA is not recommending that clinicians stop prescribing this medication. The early communication indicates that the FDA is considering but has not reached a conclusion about whether any regulatory action is warranted.
A recently published retrospective study, which prompted the investigation, reports an increased risk for serious bleeding events and death in patients with sepsis. Baseline bleeding risk factors in patients who received drotrecogin alfa activated were also reported (Gentry et al. Crit Care Med. 2009;37[1]:19-25.), according to an alert sent today from MedWatch, the FDA's safety information and adverse event reporting program. Serious bleeding events occurred in 7 (35%) of 20 patients who had a risk factor for bleeding compared with 2 (3.8%) of 53 patients without bleeding risk factors. Of the patients with baseline bleeding risk factors, more died (13 [65%] of 20 patients) vs patients without any bleeding risk factors (13 (24.5%) of 53 patients). Study limitations include its retrospective design and its small patient population.
The "contraindications" section of the drug's prescribing information says that Xigris should not be used "in the following clinical situations where bleeding could lead to significant morbidity or death":
- Active internal bleeding
- Recent (within 3 months) hemorrhagic stroke
- Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma
- Trauma with an increased risk of life-threatening bleeding
- Presence of an epidural catheter
- Intracranial neoplasm or mass lesion or evidence of cerebral herniation


Platelets Influence Vascularized Organ Transplants From Start to Finishhttp://www.medscape.com/viewarticle/586001




Abstract
This review relates the basic functions of platelets to specific aspects of organ allograft rejection. Platelet activation can occur in the donor or recipient before transplantation as well as during antibody- and cell-mediated rejection. Biopsies taken during organ procurement from cadaver donors have documented that activated platelets are attached to vascular endothelial cells or leukocytes. In addition, many patients waiting for transplants have activated platelets due to the diseases that lead to organ failure or as a result of interventions used to support patients before and during transplantation. The contribution of platelets to hyperacute rejection of both allografts and xenografts is well recognized. Intravascular aggregates of platelets can also be prominent in experimental and clinical transplants that undergo acute antibody or cell-mediated rejection. In acute rejection, platelets can recruit mononuclear cells by secretion of chemokines. After contact, monocytes, macrophages and T cells interact with platelets through receptor/ligand pairs, including P-selectin/PSGL-1 and CD40/CD154. There is a potential for therapy to inhibit platelet mediated immune stimulation, but it is counterbalanced by the need to maintain coagulation in the perioperative period.

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Stroke Awareness Campaign Aims to Halve Deaths in UKhttp://www.medscape.com/viewarticle/588041

Deaths from strokes can be halved if people recognise the signs of an attack and call an ambulance immediately. New clot-busting treatments can produce "Lazarus-like" effects and have patients up and about within a day if administered within three hours of a stroke..Stroke is the third-leading cause of death in Britain, killing 67,000 people a year. It the single largest cause of adult disability with around 150,000 people suffering a stroke annually.
Adverts will tell people to dial 999 immediately if they see one of three visible symptoms -- a drooping face, paralysed arms or slurred speech.Using the acronym FAST -- Face, Arms, Speech, Time -- it aims to raise public awareness of stroke symptoms to a similar level to that for heart attacks.
Under the government's National Stroke Strategy, patients with a suspected stroke should get an immediate scan on arrival at hospital. This will determine whether a clot is stopping blood reaching the brain or there has been a haemorrhage. Patients with a clot will be given a thrombolytic drug while those with internal bleeding may be referred to a neurological unit.




A Growing Epidemic: Special Issue of Stroke Focuses on Disparities in Care and Outcomes in Womenhttp://www.medscape.com/viewarticle/588322


The clinical presentation of stroke is the same in men and women, and stroke risk increases with increasing age in both men and womenThey found that women were significantly older than men at their first-ever stroke (average age, 75.1 years vs 71.1 years; P < .001). Women had a higher stroke risk above 85 years of age and a lower risk than men at all other ages but had a higher lifetime risk for stroke at all ages.
There were no differences in stroke subtype, severity, or case fatality rates, but women were significantly more disabled prior to stroke and in the acute phase of stroke in functions such as dressing, grooming, and transfer from bed to chair. At 3 to 6 months after the stroke, women were still significantly more disabled, more likely to be single, and 3.5 times more likely to be institutionalized.The push to look at the particular challenges posed to women by stroke and heart



Regular Aspirin Use Reduces Risk for Colorectal Cancer Precursors
http://www.medscape.com/viewarticle/588271

The results of observational studies and randomized trials suggest that regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the risk of developing colorectal adenomas, which are known precursors to colorectal cancer.An observational follow-up of the Aspirin/Folate Polyp Prevention Study (AFPPS), the researchers found that the risk for all adenomas was substantially reduced among patients who continued to use aspirin after 3 years. In addition, the chemopreventive effect of aspirin strengthened when used for at least 4 days per week.Not only did prolonged and frequent use of aspirin have a strong beneficial effect, it did not lose its efficacy with continued use. A pooled analysis showed a statistically significant 17% decrease in the relative risk for adenoma for aspirin in any dose, compared with placebo, which corresponds to a 6.7% absolute risk reduction.
A total of 850 participants had a posttreatment colonoscopy approximately 4 years after the study ended. The researchers observed that the protective effect of 81 mg of aspirin seen during the treatment phase of the study persisted only in participants who continued to take NSAIDs during the observational part of the trial. The risk for adenomas among frequent NSAID users (4 or more times per week) was 26.8%, compared with 39.9% among those in the placebo group who later used NSAIDs sporadically. The unadjusted absolute risk reduction was 13.1 percentage points.
They also note that the higher dose of aspirin did not confer a statistically significant reduction in adenoma risk during the randomized treatment phase and, in this analysis, people randomly assigned to high-dose aspirin and who later became frequent users had a nonstatistically significantly lower risk for all adenomas, compared with placebo users who became, at most, sporadic NSAID users (30.6% vs 39.9%). The small numbers of end points limited analysis for advanced lesions, but results suggested a protective effect for 81 mg of aspirin, regardless of posttreatment NSAID use.
J Natl Cancer Inst. 2009;101:256-266, 267-276.




Clopidogrel Gene Mutation Linked to Higher Rate of Stent Thrombosishttp://www.medscape.com/viewarticle/588262

A polymorphism in one of the genes responsible for metabolizing clopidogrel to its active form has been shown to be associated with an increased risk of stent thrombosis in patients undergoing PCI. The mutant *2 allele of the CYP2C19 gene occurs with a frequency of about 15%. In the current study, 25% of patients had one copy of the genotype (ie, were heterozygous) and 2% of the group were homozygous. Patients who were heterozygous had an increased risk of stent thrombosis compared with those without this genotype, and those who were homozygous had a higher risk again.
In the current study, 2485 consecutive patients undergoing coronary stent placement after pretreatment with 600 mg of clopidogrel were genotyped. The primary end point of the study was the incidence of definite stent thrombosis within 30 days following PCI. Of the patients studied, 1805 (73%) were CYP2C19 wild-type homozygotes (*1/*1), 633 (25%) were CYP2C19*2 heterozygotes (*1/*2), and 47 (2%) were homozygous (*2/*2) for the mutant CYP2C19*2 allele. The cumulative 30-day incidence of stent thrombosis was significantly higher in CYP2C19*2 allele carriers compared with those without this polymorphism. In addition, the incidence of ST-segment-elevation MI (STEMI) and ischemic stroke was significantly higher in CYP2C19*2 allele carriers vs CYP2C19 wild-type homozygotes.The risk of stent thrombosis was highest (2.1%) in patients carrying two of the mutant CYP2C19 alleles (*2/*2 genotype), and the p value for this trend was significant (p=0.002).




Coffee Intake Associated With Decreased Stroke Risk in Women
http://www.medscape.com/viewarticle/588403

A new analysis of data from the Nurses' Health Study shows that long-term consumption of up to 4 or more cups of coffee per day was not associated with an increased risk for stroke and actually appeared to be protective against stroke in women who did not also smoke. Among women who currently smoked, there appeared to be no effect of coffee intake, neither raising nor lowering stroke risk. No association was seen with other caffeinated drinks, including tea or soft drinks, and decaffeinated coffee still showed a trend toward a protective effect.
Recently reported data have suggested that coffee does not increase the risk for coronary heart disease and may be protective against type 2 diabetes, the authors write. Data on the relationship of coffee intake and stroke are "sparse," they note, and have been somewhat contradictory. In this study, they analyzed data from the Nurses' Health Study, a prospective cohort of 83,076 women who were free of stroke, coronary heart disease, diabetes, or cancer at baseline. Coffee consumption was assessed first in 1980 and then every 2 to 4 years thereafter, with follow-up over 24 years through 2004.
Over this period, 2280 strokes occurred among the women: 1224 ischemic strokes, 426 hemorrhagic strokes, and 630 strokes of undetermined cause. After adjustment for factors including age, smoking status, body-mass index, physical activity, alcohol intake, menopausal status, hormone therapy, aspirin use, and dietary factors, they found no increase in the risk for stroke associated with increasing coffee intake, and evidence for a protective effect for intakes of 2 or more cups per day vs less than 1 cup per month (P for trend = .003)



Warfarin Does Not Reduce Thromboses in Cancer Patients With Catheters: WARP Results
http://www.medscape.com/viewarticle/588368
A large study of warfarin thromboprophylaxis in cancer patients with central venous catheters (CVCs) has found that the anticoagulant did not reduce the rate of thrombotic events, either overall or related to the catheter. There was also no effect on overall survival.The results from the study, known as the WARP (warfarin prophylaxis) trial, clearly fit with guidelines from the American Society of Clinical Oncology and other bodies, which state that the use of any anticoagulant is not recommended in cancer patients with CVCs.
It is well recognized that cancer patients have an increased risk for venous thromboembolism, but routine use of thromboprophylaxis in cancer patients is still a matter of debate among clinicians.This already-raised risk of thromboembolism is increased further with the use of a CVC to administer chemotherapeutic agentsHowever, more recent trials have failed to show appreciable benefits. To some extent, the difference between the older studies showing a benefit and the newer ones showing no advantage may be partly explained by the improvements that have been made in catheter technology.
Dose-adjusted warfarin was superior to fixed-dose warfarin in preventing catheter-related thromboses (13 [3%] vs 34 events [7%]; P = .002), but it was associated with significantly more major bleeding events (7 vs 1; P = .07).
Patients may be considered for thromboprophylaxis, such as those with a personal or family history of thrombosis, carriers of thrombophilia, and those treated with chemotherapy that is known to increase the risk for thromboembolism. For these selected patient populations, the use of a low-molecular-weight heparin is recommended..
Lancet. 2009;373;523-524, 567-557. Abstract, Abstract





ISC 2009: Stroke Patients Arriving Within "Golden Hour" More Likely to Get tPAhttp://www.medscape.com/viewarticle/588456

A greater proportion of patients who arrive at the hospital in the first 60 minutes after symptom onset - the so-called "golden hour" - receive thrombolytic therapy than those who arrive later, new data from the Get With The Guidelines-Stroke (GWTG-S) quality-improvement program shows. In this analysis, 12% of all ischemic stroke patients seen at 100 GWTG-S hospitals arrived within 1 hour of symptom onset, and 27.1% of these were treated with tissue plasminogen activator (tPA) vs 12.9% of those arriving between 1 and 3 hours after onset.
"These findings support greater public-education efforts to increase the proportion of patients arriving in the first 60 minutes after symptom onset and a revamping of our hospital's performance-improvement activities to shorten the DTN times in patients who've done their part in arriving in the first 60 minutes, to make sure we do our part and get drug started for them in the next 60 minutes,.
The benefit of intravenous (IV) tPA in acute ischemic stroke is strongly time dependent, Therapeutic yield of treatment is maximal in the first minutes after stroke and declines steadily during the first 3 hours. "Every minute that goes by without treatment, 2 million nerve cells die," he said. "Every 10 minutes that goes by without tPA, 1 fewer patient experiences benefit from tPA."Patients who present within the first 60 minutes after symptom onset have the greatest opportunity for benefit from treatment, but these patients have not been well characterized. "That's why we undertook this study," Dr. Saver said.
They used the GWTG-S registry, a national database of acute strokes treated at participating hospitals in the United States. From 905 participating hospitals, a total of 517,000 stroke and transient ischemic attack patients were entered in the database between April 2003 and December 2007. After excluding those who did not arrive directly at the emergency department by ambulance or private vehicle, those having hemorrhagic strokes, and patients for whom a time of symptom onset could not be documented, they were left with 106,924 patients for this analysis.
Of these, 28.3% arrived at the hospital within 60 minutes of symptom onset; the mean onset-to-
International Stroke Conference 2009: Abstract 31. Presented February 18, 2009.
http://www.medscape.com/viewarticle/588489




Prediction of Initial Dose of Warfarin Aided by Genetic Testing

http://www.medscape.com/viewarticle/588489

An algorithm incorporating genetic information is helpful in predicting the appropriate initial dose of warfarin in patients who are "outliers"--that is, those who require either higher- or lower-than-average doses of the drug, new research has found [1]. The study showed that up to half of all people are outliersThe results are important because of the difficulty involved in establishing an initial dose of warfarin, which can vary by a factor of 10 among patients. Genotyping one can accurately predict the appropriate warfarin dose compared with empiric 'seat-of-the-pants' standard dosing.
Variations in two genes--CYP2C9 (which produces cytochrome P450, the enzyme that metabolizes warfarin) and VKORC1 (which codes for vitamin-K epoxide reductase, a key target of warfarin)--have previously been shown to influence individual responses to warfarin. In 2007, the FDA added pharmacogenetic information regarding these two genes to the warfarin product label, but it did not propose a specific method for using genetic information to predict the dose required in individual patients. In the new study--which is by far the largest and most inclusive of its kind to date, data from 4043 patients from many ethnic groups in nine countries were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical data.
They then used a validation cohort of 1009 subjects to evaluate the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose. The pharmacogenetics algorithm accurately identified larger proportions of patients who needed 21 mg of warfarin or less per week to achieve the target international normalized ratio (INR) than did the clinical algorithm (49.4% vs 33.3%; p<0.001). The same was true for those who required 49 mg or more per week--24.8% were identified using the pharmacogenetics algorithm compared with 7.2% (p<0.001) using the clinical algorithm. These two groups of "outliers" constituted almost half--46.2%--of the entire population of the validation cohort.
New Warfarin Genotyping Test Gets FDA Nod
Sparks, MD - Separately, the FDA has just approved a new test, the eQ-PCRTM LC Warfarin Genotyping Kit (TrimGen), that checks for variants in CYP2C9 and VKORC1. The assay will be used to help doctors identify who might be at risk for warfarin sensitivity, the company says [4]. Other firms have received FDA clearance for similar warfarin sensitivity tests over the past 18 months, including Nanosphere, Autogenomics, ParagonDx, and Osmetech, notes a report on GenomeWeb.com [5].


Simple Clinical Decision Rule Aids Management of Clinically Suspected Deep Vein Thrombosishttp://www.medscape.com/viewarticle/588448
Although many patients present to primary care practices with symptoms consistent with lower-extremity DVT, up to 90% of these patients referred to noninvasive testing do not have thrombosis. The authors of the current study previously examined the use of a clinical risk score as well as serum D-dimer testing to help rule out DVT more effectively in primary care. The simple clinical scale assigned 1 point of risk for each of the following factors: male sex, active cancer in the last 6 months, surgery in the previous month, absence of leg trauma, and distension of collateral leg veins. A difference in calf circumference of 3 cm or more counted for 2 points, and a positive D-dimer qualitative test was worth 6 points.
Use of this clinical tool was previously demonstrated to effectively rule out over 99% of cases of suspected thrombosis among low-risk adults. The current study seeks to validate the clinical decision rule in primary care practices.
Study Highlights
- Approximately 300 general practitioners referred patients into the study between 2005 and 2007.
- Study participants were consecutive patients from primary care practices with at least 1 of the following 3 lower extremity symptoms: swelling, redness, or pain. Patients younger than 18 years or who were receiving anticoagulant treatment were excluded from study participation.
- All patients completed the clinical decision criteria described above for DVT, including the qualitative capillary D-dimer test. If the clinical decision rule score was 3 or lower, patients were not referred for ultrasonography of the lower extremity, whereas patients with a score of 4 or higher were referred for ultrasonography.
- All patients revisited their primary care clinician at 5 to 9 days after their initial presentation to reevaluate their symptoms. Patients received a questionnaire at 3 months addressing symptoms and signs of DVT.
- The main study outcome was the usefulness of the clinical decision rule plus the D-dimer test in predicting the absence of symptomatic thrombosis (including DVT and pulmonary embolism) at 3 months.
- 1028 patients provided data for study analysis. The mean age of participants was 57.7 years, and 37% were men. 87% and 78% of patients reported leg pain and swelling, respectively. The median duration of symptoms was 5 days.
- 49% of patients had a clinical score of 3 or lower. During 3 months of follow-up, 1.4% of these participants developed venous thromboembolism.
- 49% of patients had a clinical score of 4 or higher. Of these patients, 25% had an ultrasound that was positive for DVT. Among the 374 participants with a normal ultrasound in this group, only 1.1% developed venous thromboembolism during follow-up.
- Neither patient history and physical examination nor D-dimer testing alone was sufficient to rule out DVT. Using only a cutoff of a score of 3 or fewer points on the history and examination portion of the decision tool would miss 9.6% of patients with DVT. Using only a negative D-dimer test as the decision-maker to avoid ultrasonography would miss 3.4% of patients with DVT.





New Review Finds Risk of VTE From Flying is Low http://www.medscape.com/viewarticle/588606


The risk of venous thromboembolism (VTE) associated with air travel is low, a new review on medical issues associated with commercial flights concludes [1]. The rate of DVT in one study of 9000 business travelers over four and a half years was one case for every 4500 flights. Although studies overall do show an association between VTE and long-haul flights, with risks of up to fourfold, results vary depending on the study methods, he said.
One systematic review calculated a pooled odds ratio of 1.59 for VTE from case-control studies and a relative risk of 2.93 from several prospective controlled cohort studies. These results are consistent with another population-based study (MEGA) that showed an OR of 1.7. The risk of pulmonary embolism (PE) is "even less".
Risk increases with greater number of flights within a short space of time, certain risk factors "dramatically increase the risk," business-class vs economy class travel has no effect on VTE incidence, and "immobility comes through, time and time again, as probably the biggest culprit," with the highest incidence of VTE seen in those in seats not on the aisle, he says. Risk factors that are known to increase the risk of VTE associated with flying include: obesity, recent surgery, use of oral contraceptives--which increased the risk 16-fold in one study--and presence of factor V Leiden, which increased the risk 14-fold.
Recommendations to reduce the risk of developing VTE during air travel "are based more on common sense than on evidence," say the researchers; they include being well-hydrated, reducing alcohol and caffeine consumption, changing positions or walking throughout the cabin, and doing periodic calf-muscle exercises to reduce venous stasis. Use of graduated compression stockings with an ankle pressure of 17 to 30 mm Hg can reduce risk.Cardiac, neurological, and respiratory complaints are the most serious, and while passengers older than 70 years have the highest rates of these events, the mean age of such passengers is 44 years for men and 49 years for women.




Prasugrel Approved in Europe
http://www.medscape.com/viewarticle/588602

February 23, 2009 (Indianapolis, Indiana) - The European Commission today granted marketing approval of prasugrel (Lilly/Daiichi Sankyo) for the prevention of atherothrombotic events in patients with ACS undergoing PCI [1].
The approval is based largely on the pivotal Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38). As previously reported by heartwire, the TRITON study showed that prasugrel significantly reduced ischemic events compared with clopidogrel, but at the expense of an increase in major bleeding in ACS patients scheduled for PCI.Prasugrel will be marketed in Europe as Efient.
1. European Commission approves EFIENT (prasugrel) for patients with acute coronary syndrome undergoing PCI [press release]. February 23, 2009. Available at http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=366955.



Predicting Thrombosis in Systemic Lupus Erythematosushttp://www.medscape.com/viewarticle/585634
Clotting is a serious complication of systemic lupus erythematosus (SLE) for several reasons. First, clotting can cause persistent disability and death or fetal loss in pregnant women. Second, the clinical manifestations of clotting are often misleading in patients with SLE, leading to inappropriate drug use and delayed administration of anticoagulation. Third, although positive test results for antiphospholipid antibodies and lupus anticoagulant can predict lupus-associated disability,[1] routine tests that reliably predict clotting events in these individuals have not been established. In a recent issue of the Clinical Journal of the American Society of Nephrology, Wu and colleagues sought to address this problem by evaluating the use of routinely measured D-dimer levels to predict clotting events in 100 consecutive patients enrolled in the Ohio SLE study.[2] The Ohio SLE study is a unique prospective, longitudinal evaluation of multiple biomarkers in patients with recurrently active SLE. Wu and colleagues hypothesized that elevated levels of D-dimer would predate and, therefore, predict clinical manifestations of thrombosis.
During follow-up, 15 of 100 patients assessed by Wu et al. exhibited signs or symptoms of incident thromboembolic events including pulmonary embolism, arterial thrombosis, unexplained hypoxic lung injury, microangiopathic antiphospholipid syndrome, Libman-Sacks endocarditis-related embolism, and thrombotic microangiopathic hemolytic anemia. The major conclusion of the authors was that all patients with SLE who experienced clotting had elevated D-dimer levels long before or shortly before the clinical diagnosis of the clotting event. Of the 15 patients who had evidence of thrombosis, 14 had D-dimer levels greater than 2.0 µg/ml (<0.5 µg/ml being considered a normal or negative result). By contrast, the presence of antiphospholipid antibodies or lupus anticoagulant could not reliably predict the time of clotting, as these markers were usually not abnormal within 6 months before the clinical diagnosis of the clotting event. However, combining the D-dimer assay results with measurements of these other two markers increased the sensitivity and specificity for prediction of a clotting event to 100% and 78%, respectively, with a positive predictive value of 0.5 and a negative predictive value of 1.0.
The negative predictive value of D-dimer levels reported by is in line with the results of previous studies that demonstrated the capacity of the D-dimer assay to exclude clotting at a given time point and to predict recurrent clotting events in other disease settings.[3] Hence, the D-dimer assay is potentially useful in the management of patients with SLE who present with symptoms such as shortness of breath, headache, atypical skin lesions, acrocyanosis, hemolysis, new-onset hypertension or decline of renal function, as the differential diagnosis of these conditions always includes clotting events. In such cases, a negative D-dimer assay result can rule out thrombosis as the cause of symptoms.
Furthermore, a positive D-dimer assay result predicts future clotting events in patients with SLE who lack symptoms of thrombosis. A D-dimer level greater than 2.0 µg/ml was associated with a 42% risk of a future clotting event. However, their conclusion that elevated D-dimer levels discovered on routine measurements should lead to a careful evaluation for subclinical thrombosis is not fully supported by their data. Most patients with D-dimer levels greater than 2.0 µg/ml did not experience clotting during the observation period, or they had a positive test result years before clotting became evident. Furthermore, the clinical benefits of a predictive biomarker are most evident when the prevention of negative outcomes (e.g. clotting-related damage) by biomarker-based intervention (e.g. anticoagulation) outweighs the potential increase in complications caused by intervention (e.g. anticoagulation-associated bleeding). This issue was not addressed by Wu and colleagues. Finally, a more detailed analysis of the predictive value of D-dimer testing in the subgroups of patients with membranous lupus nephritis (n = 21) or nephrotic syndrome (n not reported) would have been interesting. Patients with nephrotic syndrome are at increased risk of thrombosis, and previous risk-benefit assessments support the use of oral anticoagulation in patients with nephrotic syndrome who have membranous glomerulonephritis and a serum albumin level of less than 20 g/l.[4] D-dimer assay results might, therefore, be of particular value in refining risk estimates of thrombosis in patients with nephrotic syndrome and membranous lupus nephritis.
The data presented by Wu et al. clearly support the use of the D-dimer assay to rule out clotting or to identify future clotting risk in patients with SLE. Whether positive D-dimer results can be cost-effectively and safely used as an indication for extended diagnostic tests or for preventive anticoagulation in patients with SLE who do not present with signs and symptoms of clotting events remains to be evaluated.



Four Health Behaviors Combined Help Predict Stroke Incidence
Lifestyle behaviors such as smoking, physical activity, diet, and alcohol intake can influence cardiovascular risk, but the role of these behaviors in influencing risk in the general population is not well known. For example, other studies have reported a decrease in the incidence of myocardial infarction associated with reduction in cigarette smoking.
This is a longitudinal prospective cohort study to examine the impact of adherence to the modifiable behaviors and the risk for stroke in community-dwelling men and women in 1 region of the United Kingdom who were followed up in the European Prospective Investigation of Cancer-Norfolk study.
Study Highlights
- Included were 20,040 men and women aged 40 to 79 years at baseline recruited from an age-sex register of general practitioners with a population-based sampling frame.
- At baseline from 1993 to 1997, patients completed a detailed health and lifestyle questionnaire and listed medical conditions.
- The lifestyle behaviors examined were smoking, alcohol intake, intake of fruits and vegetables verified by vitamin C levels, and physical activity.
- 4 separate categories were used for alcohol intake.
- 1 unit of alcohol was defined as 8 g and equivalent to a half pint of beer or a glass of wine, or a unit of spirits (liquor) and total alcohol consumption were estimated as units consumed per week.
- A moderate drinker was defined as someone drinking 1 or more units per week but less than 14 units per week.
- Physical activity was assessed during the previous year and was validated against heart rate monitoring.
- A physically inactive person was defined as having a sedentary job with no recreational activity.
- A physically not inactive person was defined as a person with any activity above that of a physically inactive person.
- Trained nurses made anthropomorphic measurements, and a blood level for vitamin C was determined as a biomarker of fruit and vegetable intake.
- Participants scored 1 point for each positive behavior: currently not smoking, physically not inactive, moderate alcohol intake (1 - 14 units per week), and plasma vitamin C concentration of 50 µmol/L or higher indicating vegetable and fruit intake of at least 5 servings a day.
- The score range was 0 to 4 for combined health behaviors.
- Incident cases of stroke were ascertained by death certificate data and hospital record linkage, and trained nosologists coded death certificates.
- There were 599 strokes during 229,992 person-years of follow-up (average, 11.5 years).
- Of the stroke cases, 28% were fetal.
- Among participants, mean age was 58 years, almost half were men, BMI was 26.5 kg/m2, mean systolic blood pressure was 135 mm Hg, and total cholesterol concentration was 6.2 mmol/L.
- In the sample, men were older, had higher BMI and higher systolic blood pressure, and were more likely than women to be current or former smokers.
- The also consumed more alcohol weekly, were more physically active, and were less likely to consume 5 or more servings of fruits and vegetables daily.
- A significantly higher proportion of women scored 4 for combined health behaviors vs men, but the incidence of stroke was not significantly different for men vs women.
- The risk for stroke increased in a linear fashion for every 1-point decrease in combined health behavior score.
- Men and women who scored 0 for combined health behaviors had a 2.3 times increased risk for stroke (relative risk, 2.31) vs those who scored 4.
- The findings were consistent after adjustment for age, sex, BMI, and social class.
- The absolute risks for incident stroke were 1.7%, 2.4%, 4.0%, 6.1%, and 5.8% for health behavior scores of 4, 3, 2, 1, and 0, respectively.
- The relative risks for stroke vs those with a score of 4, after adjustment, were 1.15 for a score of 3 health behaviors, 1.58 for a score of 2 health behaviors, 2.18 for a score of 1 health behavior, and 2.31 for a health behavior score of 0.
- The authors concluded that the combined impact of 4 modifiable lifestyle behaviors resulted in a significant reduction in the risk for stroke for both men and women.

Donna Castellone

About the Author

Donna Castellone,
MS, MT(ASCP)SH
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