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PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

 

Reporter: Aviva Lev-Ari, PhD, RN

 

Q&A Session between Dr. Michael Ward and Dr. Larry Bernstein presented for in our Research Category on 

Interviews with Scientific Leaders

Primary research:

Ang L, et al “Elevated plasma fibrinogen rather than residual platelet reactivity after clopidogrel pre-treatment is associated with an increased ischemic risk during elective percutaneous coronary intervention” J Am Coll Cardiol2013; 61: 23-34.

 

Question by DR. MICHAEL WARD

How ironic that an old diagnostic parameter should
reappear in the limelight of diagnostic predictors.

Of course, decades ago, doctors asked for “sed rates”, seeking to know if red cells, thought to be bound to fibrinogen, settled faster in a patient compared to a control subject’s blood. Fibrinogen has always been a diagnostic number in evaluating inflammatory results.

However, the diagnostic world, like the worlds of pharmaceuticals, medical devices, biologics, and other industries, always seek the ‘new kid on the block’ to differentiate themselves from the rest of the pack in the
marketplace.

So there was a binge (and still is) to seek new and exotic blood proteins that are surrogate markers for specific diagnoses or prognoses.

That is the irony, that in this case at least, fibrinogen has come full circle. Biology works in mysterious ways.

Answer by Dr. Larry Bernstein, MD, FCAP

Dear Dr. M.  Ward:

Doctors asked for “sed rates”, seeking to know if red cells, thought to be bound to fibrinogen, settled faster in a patient compared to a control
subject’s blood. Fibrinogen has always been a diagnostic number in evaluating inflammatory results.

You are quite right that physicians used “sed rates” as a measure of inflammation, and more in Lupus Erythematosis, Rheumatoid Arthritis, Nephritides, Systemic Sclerosis, and so forth.  The “sed rate” was not a part of the thinking about CVD, and PCI didn’t exist.  Recently, MI post-PCI has been defined as a type (NSTEMI?).

Yes. In principle, the sed rate is related to fibrinogen and red-cell aggregation.  I am not prepared to accept that a platelet count over 400,000 would make no contribution, even if many of the PCI related infarcts are within a range of 150-300,000.  I don’t know how much power there is in the discussion.  The role of tissue factor (plaque), and of platelets in hemostasis is undeniable.

The industry does look for every opportunity to seize on promising biomarkers.  The coagulation assays developed at Dade-Behring (Dade, Dupont Division; then Dade) were far better and more explanatory that the “sed rate”.  The sed rate measurement requires that you set up graduated tubes to watch the rate of sedimentation.  It is not a walkaway procedure.  Industry has been so good at introducing automation that led to high volume efficiency, that this led to the only part of hospital operations that had good accounting measures.  The long trip to reducing personnel, but of course the profiles were a piece of cake.  I continually reorganized to carve out services for immunology and toxicology, which took longer to get automated.

The only use for sed rate now is for Temporal Thrombosis (?).

In the early days Yale NH Hospital had some 5 Perkin Elmer HPLCs to measure calcium.  Electrophoretic separation of isoenzymes was not helpful for managing patients.  The procedure was run batchwise once a day.  I was the first in CT to be running the immunoassay three times a day on the Roche COBAS Bio CFA., and Dupont put it on the ‘aca’.  A med tech could run it at 3 am  at Detroit Receiving, Bellevue, or Cook County, when the phone didn’t stop ringing for STAT results.

Physicians had expectations too.  So we had the progression from AST, LDH, and CK to isoenzyme MBCK, and then there were the cancer biomarkers – CEA, CA-125, PSA, with much to be discussed.

 

Q&A is derived from the following Article in

MedPage Today

Published: January 07, 2013

Fibrinogen Level Tied to Poorer PCI Outcomes

By Todd Neale, Senior Staff Writer, MedPage Today

Published: January 07, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

An elevated serum fibrinogen level predicted worse short-term ischemic outcomes among patients undergoing elective percutaneous coronary intervention after pretreatment with clopidogrel, researchers found.

Significantly higher levels of fibrinogen were seen in patients with periprocedural myocardial infarction (MI) defined by either creatine kinase-myocardial band (CK-MB) or troponin (P<0.02 for both), according to Ehtisham Mahmud, MD, of the University of California, San Diego, and colleagues.

Those relationships remained consistent after adjustment for several factors, including platelet function, which was not itself associated with periprocedural MI, the researchers reported in the Jan. 8 issue of the Journal of the American College of Cardiology.

“The results of the current study suggest that an elevated fibrinogen level…is related to significant platelet cross-linking and thrombus formation independent of residual P2Y12 receptor-mediated platelet activity during clopidogrel therapy,” they wrote.

Higher risk of ischemic cardiovascular events has been observed with both high platelet reactivity after thienopyridine treatment and elevated serum fibrinogen.

“As an acute phase reactant involved in the final common pathway of the coagulation cascade and essential component of platelet cross-linking in thrombus formation, fibrinogen possesses a clear biological mechanism for its adverse cardiovascular effects,” Mahmud and colleagues wrote.

In fact, high levels of serum fibrinogen have been shown to contribute to high platelet reactivity during clopidogrel treatment, resulting in uncertainty about whether insufficient platelet inhibition and elevated fibrinogen levels are independent or interactive risk factors for ischemic events.

To explore the issue, the researchers looked at data from 189 patients undergoing elective PCI who were pretreated with clopidogrel, defined as 75 mg daily for at least 7 days or a 600-mg bolus at least 12 hours before study enrollment. The mean age of the patients was 63.8 and most (74.1%) were male.

Nearly two-thirds (63%) had undergone a previous PCI, and 18% had undergone revascularization with coronary artery bypass grafting (CABG).

Baseline platelet function was measured using the VerifyNow P2Y12 assay. Markers of ischemic myocardial injury, including troponin and CK-MB, were measured every 8 hours after PCI until hospital discharge.

Periprocedural MI defined by troponin I or T occurred in 13.9% of patients. Those who had an MI had significantly higher levels of fibrinogen (363.1 versus 309.1 mg/dL, P=0.017).

The rate of CK-MB-defined periprocedural MI was 5.8%. Patients with that outcome also had elevated levels of fibrinogen (403.4 versus 313.5 mg/dL, P=0.007).

Both differences remained significant after multivariate adjustment that accounted for platelet function and other inflammatory markers.

The researchers found that a fibrinogen level of 345 mg/dL or higher — a cutoff identified as having optimal combined sensitivity and specificity for CK-MB-defined periprocedural MI — was associated with periprocedural MI defined by either troponin or CK-MB (P<0.04 for both).

Those relationships were stronger when systemic inflammation was low (C-reactive protein ≤0.5 mg/dL).

The platelet reactivity measurements were not associated with either definition of periprocedural MI, which is inconsistent with the findings from several smaller studies. The authors noted, however, that “the significance of these negative findings may be limited due to inadequate study power.”

In discussing the limitations of the study, the researchers pointed out that “the findings … do not provide insight into whether the relationship between high platelet reactivity and ischemic cardiovascular events demonstrated in previous studies is a direct one or mediated through the effect of serum fibrinogen.”

To get to the bottom of that, they wrote, “future studies relating platelet reactivity and adverse cardiac events should measure baseline fibrinogen.”

Mahmud has received clinical trial support from Accumetrics, Eli Lilly, and sanofi-aventis, and is on the speakers bureau for Medtronic. One of his co-authors is a consultant for Abbott Vascular, Boston Scientific, St. Jude Medical, Medtronic, and sanofi-aventis.

From the American Heart Association:

Todd Neale

Senior Staff Writer

Todd Neale, MedPage Today Staff Writer, got his start in journalism at Audubon Magazine and made a stop in directory publishing before landing at MedPage Today. He received a B.S. in biology from the University of Massachusetts Amherst and an M.A. in journalism from the Science, Health, and Environmental Reporting program at New York University.

SOURCE:

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Reporter: Aviva Lev-Ari, PhD, RN

NEW YORK (GenomeWeb News) – The Alzheimer’s Association and the Brin Wojcicki Foundation yesterday announced a partnership aimed at obtaining the whole-genome sequences of people with AD.

The Alzheimer’s Association and the Wojcicki Foundation are funding the project, which seeks to perform whole-genome sequencing on more than 800 people enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), generating at least 165 terabytes of new genetic data.

Once the genomes are sequenced, the raw data will be made available to scientists worldwide to investigate new targets for risk assessment and new therapies and to gain new understanding into the disease, which afflicts an estimated 5.4 million Americans.

“The current ADNI database already includes detailed, long-term assessments of neuropsychological measures, standardized structural and functional imaging, and precise biomarker measures from blood and spinal fluid,” said Robert Green of Brigham and Women’s Hospital and Harvard Medical School, and who will coordinate the sequencing work within ADNI. “Adding whole-genome sequences to this rich repository will allow investigators all over the world to discover new associations between these disease features and rare genetic variants, offering new clues to diagnosis and treatment.”

The new project is an extension of ADNI, a public-private research project launched in 2004 with the goal of identifying biomarkers of AD in body fluids, structural changes in the brain, and measures of memory, in order to improve early diagnosis of the disease and develop better treatments. The National Institutes of Health leads ADNI and private sector support is provided through the Foundation for NIH.

ADNI is led by principal investigator Michael Weiner from the University of California, San Francisco and the San Francisco VA Medical Center. Green will collaborate with Arthur Toga of the University of California, Los Angeles, and Andrew Saykin of Indiana University on the sequencing work.

The genome sequencing will be done at Illumina.

http://www.genomeweb.com//node/1099936?hq_e=el&hq_m=1303351&hq_l=3&hq_v=e1df6f3681

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